The Yeast Frataxin Homologue (Yfh1) DISCUSSION

The Yeast Frataxin Homologue (Yfh1) DISCUSSION
DISCUSSION 
The loss-of-function of YFH1 results in striking maldistribution of cellular iron, with depletion of cytoplasmic iron and accumulation of mitochondrial iron. Here we show that mitochondrial iron in  yfh1 cells, although present in large excess, is unavailable for haeme synthesis. Ferrochelatase, a mitochondrial protein, able to mediate insertion of iron or zinc into the porphyrin precursor, makes primarily the zinc protoporphyrin product. Zinc protoporphyrin instead of haeme accumulates during growth of  yfh1 mutant cells and, furthermore, preferential formation of zinc protoporphyrin is observed in real time. The method for these studies involves direct presentation of porphyrin to mitochondria and to ferrochelatase of permeabilized cells with intact architecture, thereby specifically testing the iron delivery portion of the haeme biosynthetic pathway. The studies show that  yfh1 mutant cells exhibit a defect in iron use by ferrochelatase.
Multiple secondary effects and the complex pleiotropic phenotype of these cells has impeded definition of the function of frataxins. The defect in haeme synthesis in Yfh1p depleted cells, however, is readily reversed by reinduction of expression from a regulated promoter, and therefore the phenotype is not due to secondary effects such as mtDNA damage. The precise role of Yfh1p and frataxins in iron delivery for haeme synthesis remains to be defined. A role for Yfh1 in iron solubilization in mitochondria is possible and/or a role in directly handing of iron as described for metallation of copper proteins by copper chaperones (29). Ferrochelatase is able to use soluble ferrous iron as a substrate for iron incorporation into PPIX, and iron is largely present as insoluble ferric particles in  yfh1 mitochondria. This could explain why the large excess of iron in these mitochondria is not available for haeme synthesis, and maybe for other iron-requiring processes like Fe–S centre assembly. The involvement of Yfh1p might involve a role in maintaining solubility of iron in mitochondria. Our results show that Hem15p and Yfh1p physically interact in vitro. An in vivo interaction between these two proteins might mediate hand-off of iron for haeme formation. Adamec et al. (30) showed that self-assembled multimers of Yfh1p can sequester more than 3000 atoms of iron, and that iron can be released from the protein shell by a reducing agent. It is tempting to speculate that iron bound to such a Yfh1p intermediate may be the iron donor to ferrochelatase for haeme synthesis. Such a donor should exist as it is unlikely that there is ‘free’ iron in mitochondria, which is an environment particularly sensitive to radical reactions.
The role of Yfh1p in iron delivery for haeme synthesis recalls the recently described role of Yfh1p in iron delivery for Fe–S cluster synthesis in mitochondria (8,15–18). The precise function of Yfh1p is likewise undefined in this process. A recent study by Puccio et al. (17) analysed the sequence of events in tissues of transgenic mice following frataxin depletion. They found that the Fe–S assembly defect appeared prior to mitochondrial iron accumulation, suggesting a primary role for frataxin in iron utilization. Our work also indicates that Yfh1 is involved in mitochondrial iron use (for haeme synthesis as for Fe–S cluster synthesis) and for correct partitioning of iron between mitochondrial and cytoplasmic pools. Definition of the mechanisms of these effects will require additional work, and the identification of additional components of the mitochondrial iron transport system(s).
The cytochrome-deficient phenotype of  yfh1 cells is often masked by nuclear mutation(s) that suppress the phenotype. The features of strains carrying such suppressor mutations are striking. Haeme synthesis is restored as indicated by complete recovery of cytochrome spectra and disappearance of Zn-PPIX. Haeme synthesis is restored, although iron accumulation and Fe–S cluster deficiency phenotypes are intermediate between the wild-type and deletion phenotypes. We frequently encountered such genetic changes with various  yfh1 strains: strains were cytochrome-deficient when freshly isolated and acquired normal pigmentation after a few culture cycles on complete medium. Our finding that  yfh1 cells accumulate suppressor mutation(s) fits well with a recent work (19), showing that the absence of Yfh1 in yeast leads to nuclear damage, increased chromosomal instability including recombination and mutation, and greater sensitivity to DNA-damaging agents. The frequency of these events may explain why the link of Yfh1p with cytochromes and haeme synthesis has not previously been described. The implication of the results is that the requirement of Yfh1p in haeme synthesis can be bypassed by nuclear gene mutations. Identifying the suppressor mutation(s) that allow(s)  yfh1 cells to recover normal cytochrome synthesis and respiration is being undertaken. The unidentified suppressor mutation(s) might result in solubilizing part of the iron accumulated into  yfh1 mitochondria, making it available for haeme synthesis, as suggested by our Mössbauer analysis. The low expression of frataxin in erythroid cells (11) and the lack of red cell phenotypes in the human frataxin deficiency disease Friedreich ataxia (11) likewise suggest that haeme synthesis can occur in the absence of frataxin in some settings.
Ferrochelatases from diverse species as mammals, Drosophila, Schizosaccharomyces pombe and some bacteria possess 2Fe–2S clusters that are critical for activity (reviewed in 31). In view of the role of frataxin in Fe–S cluster formation, an effect of frataxin deficiency on ferrochelatase function in these species might be inferred. By contrast, the ferrochelatase of S. cerevisiae lacks such as Fe–S cluster and appears to be an outlier in this regard. One can speculate about the implications of this difference for the regulatory links between frataxin and ferrochelatase function. Perhaps, the effects of frataxin on Fe–S cluster assembly being insufficient to inactivate ferrochelatase in S. cerevisiae, alternative regulatory mechanisms evolved instead. At least two such mechanisms are observed here. First, a transcriptional mechanism is implied by the decreased Hem15 transcript levels observed in the absence of Yfh1. The mediators of this response are not Aft1 or Aft2, the previously identified iron regulatory proteins (22,23). Second a post-transcriptional effect of Yfh1 is required for active ferrochelatase function. This might involve a role of Yfh1 in delivery of the substrate iron for haeme formation. Alternative possibilities are that Yfh1 activates ferrochelatase activity by producing a folding or conformational change in the protein, or by contribution of a catalytic iron atom that serves a function analogous to the regulatory Fe–S cluster. The direction of these regulatory effects makes sense in terms of coupling haeme synthesis to the availability of the critical iron cofactor. In similar fashion, the first step in haeme biosynthesis,  -aminolevulinate synthase in erythroid cells, is positively regulated by iron (32) and ferrochelatase in mammals is also regulated by iron via post-transcriptional mechanisms (33). Many questions remain: the molecular details of the regulatory effects of Yfh1 on ferrochelatase function remain to be defined. Also a question exists as to whether similar control mechanisms will be found in mammalian tissues.

The Yeast Frataxin Homologue (Yfh1) RESULTS

The Yeast Frataxin Homologue (Yfh1) RESULTS
RESULTS 
The colonies appeared depigmented and measurement of total cellular haeme revealed global haeme deficiency in the mutant cells (0.01 nmol haeme/mg dry weight) compared with the wild-type (0.2 nmol haeme/mg dry weight). Low-temperature spectra of  yfh1 mutant whole cells revealed a virtual absence of b, c and (a+a3) cytochrome signals (Fig. 1). In contrast, a signal from zinc protoporphyrin was observed in the mutant cells, and this signal was further enhanced by zinc supplementation of the growth media. This observation is significant because biosynthesis of Fe-PPIX (haeme) and Zn-PPIX both require porphyrin precursor and ferrochelatase activity, differing only in the final metal insertion step. The prevalence of Zn-PPIX synthesis rather than haeme synthesis in  yfh1 cells did not result from increased zinc accumulation in  yfh1 cells compared with wild-type cells. Actually, the total zinc content of the cells was lower in  yfh1 cells than in wild-type cells (402 µg zinc per g  yfh1 cell paste and 457 µg zinc per g wild-type cell paste). A detailed study of zinc metabolism in  yfh1 cells will be published elsewhere.
A general problem that has impeded characterization of Yfh1p function is the variability and instability of the phenotypes of the deletion strains. In part this is due to a tendancy to lose functional mtDNA, thereby becoming rho minus or rho zero. A mutator phenotype characterized by increased frequency of secondary nuclear mutations has also been associated with Yfh1p loss of function (19). Therefore, in order to distinguish primary effects from secondary changes ensuing from lack of YFH1, we created a strain in which the sole copy of YFH1 was placed under the control of a galactose inducible promoter. In this strain, regulated expression of Yfh1 allowed correlation of phenotypes with different Yfh1p expression levels. If this strain was grown in raffinose, a non-inducing carbon source, for 24 h, Yfh1p was undetectable by immunoblotting of isolated mitochondria, and the cells exhibited phenotypes similar to the  yfh1 strain. However, under these conditions, rho minus conversion or secondary genetic changes were not observed (not shown). As was observed for the deletion strain, cytochromes were undetectable in the low temperature spectra, whereas Zn-PPIX was clearly discerned as a 580 nm absorbance peak (Fig. 2). Cytochrome c was an abundant haeme protein of the intermembrane space was undetectable by blotting in these cells. When the cells were exposed to galactose, the promoter was rapidly induced and Yfh1p expression reached a maximum within 2 h. Cytochromes in general and cytochrome c in particular were recovered, although the time course of recovery seemed delayed with respect to the recovery of Yfh1p levels. Yfh1p was completely restored at the 2 h time point, whereas cytochromes recovery lagged behind (Fig. 2). The critical Yfh1p function involved in haeme formation presumably occurs during this time interval.
Loss of function of Yfh1 affects the final step of haeme synthesis
The final step in haeme biosynthesis involves iron insertion into PPIX and is catalysed by ferrochelatase, the product of the HEM15 gene. The Hem15 protein, localized to the mitochondrial inner membrane, was markedly decreased in  yfh1 mitochondria (Fig. 3A). HEM15 mRNA was also lower in the  yfh1 mutant than in wild-type cells (Fig. 3B), as also reported by others (20). Other key enzymes of the haeme pathway were unchanged in yfh1 mutant cells: the amounts of Hem1p ( -aminolevulinate synthase) and Hem13p (coproporphyrinogen oxidase) were the same as in the wild-type (Fig. 3A), and the activity of Hem14p (protoporphyrinogen oxidase) was normal (see below). These data suggested that the defect in haeme synthesis in yfh1 mutant cells might be due to low level of ferrochelatase protein. We therefore sought to correct the Hem15p deficiency by using a multicopy plasmid to increase expression of the gene in the  yfh1 strain. Surprisingly, the  yfh1 cells transformed with YEp351-HEM15 grew even more slowly than the untransformed cells, forming tiny colonies on agar plates one week after transformation (not shown). The total haeme and cytochrome contents of the transformed mutant cells remained much lower than the wild-type cells (not shown). Thus, the cytochrome defect of  yfh1 cells does not result from a lack of Hem15p. Moreover, while cytochromes were almost undetectable in  yfh1 cells, a peak of Zn-PPIX was clearly apparent in these cells (see below). Zinc is an alternative substrate of ferrochelatase (21). Thus, although Hem15p was expressed at very low levels in the  yfh1 mutant, the protein was still produced and probably functional in the mutant (see below).
An unresolved question was why Hem15 levels were low in the  yfh1 strain. HEM15 transcription was found to be regulated in an iron-dependent manner, without dependence on Aft1p or Aft2p, the iron regulatory transcription factors (22,23). As shown in Figure 3B, iron addition to the growth media was correlated with a 2–3-fold increase in transcript abundance whether or not Aft1 or Aft2 was present. In the  yfh1 strain the transcript was virtually undetectable. The molecular mediators of this iron dependent regulation remain to be determined. It is generally admitted that Aft-dependent genes are upregulated in  yfh1 cells because cytosolic iron is low in these cells, most of the iron being sequestered in the mitochondrial compartment (14). In the case of HEM15, an Aft-independent gene, downregulation of transcription was probably again mediated by alterations in cytoplasmic iron levels, but the regulatory pathway appears to be a novel one.
Iron unavailability for haeme synthesis in  yfh1 cells
Studies of in vitro haeme synthesis are often difficult to interpret, since ferrochelatase has a high affinity for ferrous iron, and in vivo iron availability to ferrochelatase probably depends on crucial factors related to iron compartmentalization or availability of an electron donor. Therefore, addition of exogenous ferrous ions and protoporphyrin IX (PPIX) to isolated mitochondria will result in haeme synthesis in vitro, even if no haeme synthesis occurred in vivo.
The level of ferrochelatase protein in  yfh1 cells was lower than in wild-type cells, although the residual protein level varied depending on the yeast genetic background from roughly 10% (X498-1A) to 25% (S150-2B yfh1) of normal. This residual ferrochelatase protein was active as shown by the presence of Zn-PPIX in the mutants. Furthermore, the residual ferrochelatase in  yfh1 mutants was able to mediate haeme formation (as measured by the pyridine haemochromogen method) when iron as ferrous ascorbate (or ferric citrate+NADH) and PPIX were added to isolated mitochondrial membranes. By contrast, haeme in  yfh1 cells (X498-1A or S150-2B) was virtually undetectable, leading us to conclude that an additional defect in iron or porphyrin availability to ferrochelatase must exist in these cells. We then developed an in vitro assay to measure endogenous iron availability to ferrochelatase, using permeabilized whole cells (Fig. 4A) or intact mitochondria (Fig. 4B). We used protoporphyrinogen instead of PPIX as the substrate of reaction, and no exogenous metals, so that only endogenous iron or zinc could be incorporated into PPIX to form haeme or Zn-PPIX. Protoporphyrinogen is the substrate of protoporphyrinogen oxidase, an inter-membrane space enzyme, which converts protoporphyrinogen into PPIX. Protoporphyrinogen and haeme are both non-fluorescent, while PPIX and Zn-PPIX are both highly fluorescent. The use of protoporphyrinogen as substrate allowed monitoring with high sensitivity the rate of PPIX and Zn-PPIX synthesis. In the presence of a metal chelator such as EDTA or 8-hydroxyquinoline, haeme and Zn-PPIX formation from PPIX was inhibited, and we measured the rate of PPIX formation from protoporphyrinogen, i.e. protoporphyrinogen oxidase activity. This activity was comparable in both wild-type and yfh1 mutant cells (Fig. 4A, left panel), showing that the porphyrin substrate for ferrochelatase was not the limiting factor for haeme synthesis. When no chelator was added, part of the PPIX synthesized could be used by ferrochelatase to form haeme or Zn-PPIX with endogenous metals. The rate of haeme synthesis can then be calculated as: total PPIX (measured in the presence of a chelator) minus (Zn-PPIX+PPIX) (measured without chelator). In the absence of a chelator, much more PPIX accumulated in  yfh1 cells than in the wild-type (Fig. 4A, middle panel), suggesting that PPIX was being produced but not utilized for haeme synthesis in the  yfh1 cells. Finally, Zn-PPIX was formed more rapidly in  yfh1 cells than in wild-type cells, consistent with the unavailability of iron as a substrate for ferrochelatase (Fig. 4A, right panel). Similar experiments were done with intact isolated mitochondria from the GAL-Yfh1 strain (galactose-dependent expression of YFH1) repressed for YFH1 expression, and induced for 2 h and 5 h with galactose (Fig. 4B). Similar activity of protoporphyrinogen oxidase was observed with all mitochondria samples (Fig. 4B, upper left panel). However, when endogenous metals were not chelated by EDTA, the rate of formation of PPIX from protoporphyrinogen decreased as YFH1 was induced (Fig. 4B, upper right panel), meaning that an increasing part of the PPIX produced was used to form Zn-PPIX and haeme as YFH1 became induced. The rate of Zn-PPIX formation with endogenous zinc was comparable in all the mitochondria samples (Fig. 4B, bottom left panel). In contrast, the availability of endogenous iron to form haeme was very low in mitochondria with repressed Yfh1, and increased after galactose induction, especially after 5 h induction (Fig. 4B, bottom right panel). This result fits well with the data of Figure 2, showing induction of cytochrome synthesis in cells of the same strain after 2 and 5 h induction of YFH1 by galactose. It is interesting to note that induction of Yfh1 expression in Yfh1-deficient cells did not result in immediate restoration of haeme synthesis and cytochrome production: while the level of Yfh1p was comparable to wild-type levels after 2 h induction by galactose, the synthesis of haeme (Fig. 4B) and of cytochromes (Fig. 2) was maximum only 5 h after induction.
Iron precipitation in an inorganic form in  yfh1 mitochondria
The observation that iron was unavailable for haeme synthesis in  yfh1 cells raised a question of why this should be so. The physical state of the iron was examined in mutant mitochondria using Mössbauer spectroscopy. Figure 5 shows Mössbauer spectra of mitochondria purified from a wild-type (YPH499) recorded at 4.3 K in a small perpendicular field of 20 mT. No Mössbauer signal was visible, indicating an iron concentration therein of lower than 300 µM and a lack of iron accumulation. In contrast, the mitochondria of the isogenic  yfh1 mutant (X498-1A) displayed a well-resolved quadrupole doublet at 4.3 K (spectrum not shown) exhibiting an isomer shift  =0.53(4) mm s-1, a quadrupole splitting  EQ=0.63(1) mm s-1 and a line width  =0.57(1) mm s-1 (numbers in brackets correspond to calculated error of last digit). No ferrous iron was observed. These Mössbauer parameters are typical of a high-spin ferric iron bound to oxygen/nitrogen in an octahedral arrangement. Very similar parameters were found for various bacterioferritins at this temperature (24–27). Mitochondria of a  yfh1 suppressor strain isolated from X498-1A (sup4+, see Fig. 5) exhibited a doublet with almost the same Mössbauer parameters ( =0.52 mm s-1,  EQ=0.67 mm s-1,  =0.53 mm s-1; not shown). However, the degree of ferric ion accumulation per gram mitochondria was approximately one-quarter of that found in the original  yfh1 strain.
A  -value of 0.57 mm s-1 indicates a line-width broadening which can be associated with relaxation or superparamagnetic phenomena. Indeed, further broadening of the Mössbauer lines [ =0.53(4) mm s-1,  EQ=0.64(1) mm s-1,  =0.73(1) mm s-1] occurred at 1.9 K (Fig. 5). Moreover, the formation of a second unstructured component (42% of absorption area) was observed. In contrast to what was found in bacterioferritins, no indication for a distinct magnetic hyperfine field or a narrow ranged field distribution was visible. This and the features of a high field spectrum (7 T, not shown) are consistent neither with a superparamagnetic transition as observed in bacterioferritins, nor with a magnetic transition of antiferromagnetically µ-oxo-coupled systems. The featureless broadening is best explained by a broad distribution of individual hyperfine fields originating from many magnetically non-equivalent ferric ions. Thus, our data are consistent with the presence of small and very amorphous nano-particles of iron in  yfh1 mitochondria. Various attempts to visualize these particles on PAGE failed. The material remained in the wells of the gel, as seen by Fridovich staining (not shown). There were only very small amounts, if any, of protein associated with these particles (0.1 µg protein/µg iron), which could represent non-specific adsorption. Phosphate and iron determination resulted in a Fe/P ratio of 1/2.9 (8). We conclude that iron was essentially present in  yfh1 mitochondria as nano-particles of ferric phosphate. In fact, an EXAFS analysis (not shown) supported the structural model of ferric phosphate as the main iron compound of  yfh1 mitochondria. A complete analysis of EPR-, Mössbauer spectroscopic and EXAFS data from whole cells and from mitochondria will be published elsewhere.
Suppressor mutations frequently mask the cytochrome defect of  yfh1 cells
Some authors described normal cytochrome production in  yfh1 cells (28). According to this observation, the cytochrome and respiratory defects reported by others for  yfh1 mutants (3) could depend on a particular genetic background, on the growth conditions, or could result from rho minus conversion of the cells. Our results, however, do not support this hypothesis. We constructed a  yfh1 shuffle strain where the yfh1 deletion was covered by a shuffle plasmid bearing a wild-type copy of YFH1. Cells of this strain formed isolated, depigmented colonies when plated on YPD+cycloheximide, but did not grow on YPG+cycloheximide plates (not shown). When  yfh1 cells from a YPD plate were inoculated in liquid medium with glycerol as the carbon source, growth was delayed by a lag of 1–3 days (not shown). The cells harvested after 5 days on glycerol medium showed a normal cytochrome spectrum, unlike cells grown on raffinose as the carbon source, which were completely depigmented (Fig. 6). Cells from the glycerol culture did not recover the original phenotype of  yfh1 (lack of cytochrome) when re-inoculated on a raffinose-based medium (Fig. 6). This result indicates that some inheritable change(s) occurred to the cells during their growth on glycerol. Indeed,  yfh1 cells accumulated suppressor mutations with high frequency, which was easily observed on agar plate. When a mat of  yfh1 cells was plated onto a YPG plate, numerous colonies grew on a background of non-growing (or poorly growing) cells (Fig. 7). The same observation was made with  yfh1 cells from different genetic backgrounds, including YPH499, S150-2B, CM3260 and W303 (not shown). We analysed several suppressor colonies of  yfh1 from various genetic backgrounds. Most of the time, the suppressor strains exhibited the same phenotype as presented in Fig. 8. Cells recovered a normal cytochrome content (Fig. 8A) and normal activity of haeme-containing enzymes such as catalase (not shown). The activity of enzymes containing an iron–sulphur cluster remained low (Fig. 8B). Ferrochelatase and cytochrome c levels were increased compared to the original  yfh1 mutant (Fig. 8C). Respiratory activity was similar to that of the wild-type (Fig. 8D). Cell iron accumulation decreased compared with the original  yfh1 mutant but was still higher than in the wild-type (Fig. 8E), and iron still accumulated in the mitochondria, although to a lesser extent than in the original  yfh1 mutant (not shown). Resistance of the cells to oxidative stress was increased (Fig. 8F). The suppressor phenotype of glycerol-growing cells resulted from nuclear mutation(s).
We crossed  yfh1 cells showing the suppressor phenotype with an original  yfh1 mutant of the same background with the opposite mating type. Features of the diploid were intermediate between the suppressor strain and the non-suppressed deletion strain, indicating semi-dominance of the suppressor mutation (Fig. 8C). Following sporulation and tetrad dissection, the suppressor phenotype was recovered in the tetrads, showing a 2:2 segregation of the suppressor characteristics (Fig. 8C). Such nuclear (semi-dominant) suppressor mutations occurred with high frequency in  yfh1 cells submitted to the selection pressure of a non-fermentable carbon source or oxidative stress. The high rate of new suppressor mutations has prevented us from identifying the suppressor gene by complementation. A genomic library was constructed from a  yfh1 suppressor strain and used to transform an original  yfh1 strain. Transformants were selected on a copper-rich medium allowing growth of suppressors but not of original  yfh1 cells. All the colonies analysed were new suppressor strains (not shown).
Thus, the presence of normal cytochrome concentration in some  yfh1 strains (28) may result from suppressor mutations rather than from adaptation of the cells to particular growth conditions. Conversely, the lack of cytochromes in  yfh1 was not a consequence of rho minus conversion of the cells, since induction of Yfh1 by galactose in the GAL-Yfh1 strain rapidly induced synthesis of all the cytochromes, with concomitant disappearance of Zn-PPIX, as shown above (Fig. 2). We conclude that Yfh1 is required for normal cytochrome synthesis in  yfh1 cells, independent from the background and from the tendency of cells to loose mitDNA.

The Yeast Frataxin Homologue (Yfh1) -ABSTRACT-INTRODUCTION

The Yeast Frataxin Homologue (Yfh1) -ABSTRACT-INTRODUCTION 
ABSTRACT  
The YFH1 gene is the yeast homologue of the human FRDA gene, which encodes the frataxin protein. Saccharomyces cerevisiae cells lacking the YFH1 gene showed very low cytochrome content. In  yfh1 strains, the level of ferrochelatase (Hem15p) was very low, as a result of transcriptional repression of HEM15. However, the low amount of Hem15p was not the cause of haeme deficiency in  yfh1 cells. Ferrochelatase, a mitochondrial protein, able to mediate insertion of iron or zinc into the porphyrin precursor, made primarily the zinc protoporphyrin product. Zinc protoporphyrin instead of haeme accumulated during growth of  yfh1 mutant cells and, furthermore, preferential formation of zinc protoporphyrin was observed in real time. The method for these studies involved direct presentation of porphyrin to mitochondria and to ferrochelatase of permeabilized cells with intact architecture, thereby specifically testing the iron delivery portion of the haeme biosynthetic pathway. The studies showed that  yfh1 mutant cells are defective in iron use by ferrochelatase. Mössbauer spectroscopic analysis showed that iron was present as amorphous nano-particles of ferric phosphate in  yfh1 mitochondria, which could explain the unavailability of iron for haeme synthesis. A high frequency of suppressor mutations was observed, and the phenotype of such mutants was characterized by restoration of haeme synthesis in the absence of Yfh1p. Suppressor strains showed a normal cytochrome content, normal respiration, but remained defective in Fe–S proteins and still accumulated iron into mitochondria although to a lesser extent. Yfh1p and Hem15p were shown to interact in vitro by Biacore studies. Our results suggest that Yfh1 mediates iron use by ferrochelatase.

INTRODUCTION 
The YFH1 gene is the yeast homologue of the human FRDA gene, which encodes the frataxin protein. Mutations of FRDA associated with decreased frataxin expression are responsible for Friedreich's ataxia, the most common autosomal-recessive neurodegenerative disease of Caucasians (1,2). Both genes code for mitochondrial proteins that are involved in iron homeostasis and cellular respiration (3–8), but their precise roles are unknown. Cardiac tissues from patients with Friedreich's ataxia exhibit iron deposition, deficiencies in many iron–sulphur cluster enzymes and reduced mitochondrial DNA (8,9). In addition, fibroblasts from these patients show hypersensitivity to oxidative stress that can be rescued by treatment with iron chelators (10). A link to haeme biosynthesis has not been uncovered, and blood, bone marrow and red cell development appear to be normal in patient with frataxin deficits. Frataxin is downregulated during erythroid development, suggesting that this protein is not involved in the high-volume iron trafficking that accompanies red cell production in the bone marrow (11). However, activities of haeme enzymes in other tissues of Friedreich's ataxia patients have not been assessed, leaving open the possibility that tissue-specific haeme deficiencies may exist.
Yeast cells lacking Yfh1p mirror many of the phenotypes observed in disease tissues from patients with Friedreich's ataxia. These cells have defective respiration (3,5,12–14), unstable mitochondrial DNA and hypersensitivity to oxidative stress (3–5). The assembly of Fe–S centres is impaired and cytochrome concentrations are low (4,8). Iron uptake is much greater than in wild-type cells, with most of the iron being found in the mitochondria (3,12). The involvement of Yfh1p in the assembly of Fe–S centres has been described in several studies (8,15–18), but no work has been devoted yet to investigate the possible specific involvement of Yfh1p in the synthesis of haeme, a major iron cofactor synthesized into the mitochondria. An impediment to understanding the function of Yfh1p or frataxin has been the complex nature of the cellular phenotypes resulting from depletion or loss of function. Here we reexamine the role of Yfh1p in iron homeostasis with special emphasis on haeme synthesis. We describe a switch from haeme synthesis to zinc protoporphyrin synthesis that occurs in absence of Yfh1p. A highly sensitive fluorimetric method is used to demonstrate this switch. Previous studies have not noted effects of Yfh1 on haeme formation in yeast, and this may be due to the high frequency of suppressor mutations that mask this phenotype. Here we describe the characteristics of such suppressor mutants, and the effects on haeme formation in the absence of Yfh1p.

Chemist, Mining Industry - Norton Industries

Chemist, Mining Industry - Norton Industries
Mining Industry
Charles Bucknam worked as a chemist at a winery and in the pulp and paper industry before joining Newmont Metallurgical Services where he now analyzes mined ores. Bucknam discovered found that training in one industry can be effectively applied to another. For example, he says, "My background from the paper industry was to do material balances. When I came to the copper mining business, I looked at the material that was going through the mill and the gold we were getting out of it, and I realized that something was going wrong. I wanted to figure out exactly how much gold we were losing." He used his knowledge of material balances to help accomplish this.
Bucknam is essentially an analytical chemist specializing in inorganic analysis. In his career, he has held a variety of positions. He has been the person in charge of instrumental analysis, measuring gold content in a number of inorganic materials; a shift supervisor, overseeing assay and quality control labs; and a member the staff in Newmont's exploration research lab. He also developed new processes for analysis of gold automated systems for sample preparation. He says his job has given him the opportunity to continuously expand his knowledge of mineral deposits and allowed him to travel and work with mining problems all over the world.
"In each job, you need to develop a working relationship between industry and government. Every new mine has its own set of problems," Bucknam explains. Often at the heart of this relationship are the environmental concerns of the region. "We work hard to develop mining processes that have a low environmental impact," he says.
Norton Industries
Tom Szymanski was drawn to inorganic chemistry. "I was fascinated that in many biological systems, the action is at the metal center," he says. Part of the general training for inorganic chemists is to look for interactions and look for cause and effect patterns, he explains. "It's a training that's widely applicable," he adds. Szymanski now works as a project manager, supervising research on ceramics used in the hydrocarbon industry. "Our expertise is to provide detailed ceramics for catalyst applications," he says. "All the systems we work on contain metal to oxygen bonds and my job is to ask myself 'what do I know about inorganic chemistry that enables me to alter the system I have so that it works better for our customers?'" he says. Most of the projects he supervises involve cooperative efforts with customers making good communication skills as important as training in the basic discipline.
Steve Feldman
Chemist
USDA Food Safety and Inspection Services
Steve Feldman has a Ph.D. in inorganic chemistry, but his job is working as an analytical chemist. Use of the latest technology in analytical chemistry is one of the things Feldman likes best about his work at USDA's Food Safety and Inspection Services. One of the projects he works on is analyzing for illegal use of the growth hormone, clenbuterol, in show animals. The hormone is used in Europe, but is banned in this country because it can cause severe allergic reactions if it finds its way into the human food supply. "The USDA tests for chemicals that get into foods and veterinary medicine," he says.
"If one eliminates education, the prospects for jobs for inorganic chemist are there, but they are not plentiful," he says. Feldman advises students of inorganic chemistry to choose courses that will broaden their knowledge, and also to get experience with analytical instrumentation such as gas chromatography, HPLC, and mass spectrometry.
Los Alamos National Laboratory
Sara Scott trained as an organic chemist. She worked in Germany as a NATO/National Science Foundation postdoctoral fellow, and then shifted the course of her career to analytical chemistry, eventually becoming a group leader for an analytical chemistry group at Los Alamos National Laboratory. She says she was ready for a change when she shifted her work to analytical chemistry and has enjoyed being in a management position. The group she manages performs analytical searches, development, and analyses of a wide variety of samples including nuclear materials, soils, dust, plastics, and alloys.
"In the environmental samples we analyze, we are looking for inorganic analyses and radio chemical components," she explains. The information gained from analysis of these environmental materials can contribute to the remediation of contaminated sites. "An important part of my work is problem solving. It's nice to be doing something tangible and to be able to show that a problem you have solved has made a difference."As a female manager in a large government lab, Scott says she has received support from her superiors. "When I took this job, I was pregnant," she says. "It never once crossed my mind that having a baby would jeopardize my career. I think it's a real credit to the management at this lab that this was not a concern for me."
Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1)
Emmanuel Lesuisse1,*, Renata Santos1, Berthold F. Matzanke2, Simon A. B. Knight3, Jean-Michel Camadro1 and Andrew Dancis3

Inorganic Chemistry, Has a Wide Range of Application

Inorganic Chemistry, Has a Wide Range of Application
Inorganic chemistry is the study of the synthesis and behavior of inorganic and organometallic compounds. It has applications in every aspect of the chemical industry–including catalysis, materials science, pigments, surfactants, coatings, medicine, fuel, and agriculture. Inorganic chemists are employed in fields as diverse as the mining and microchip industries, environmental science, and education. Their work is based on understanding the behavior and the analogues for inorganic elements, and how these materials can be modified, separated or used–often in product applications. It includes developing methods to recover metals from waste streams; employment as analytical chemists specializing in analysis of mined ores; performing research on the use of inorganic chemicals for treating soil. Many inorganic chemists go into industry, but they are also at universities and in government labs. Inorganic chemists who work in government say their time is increasingly spent writing grant proposals and competing for a small pool of research money.
Inorganic chemists compare their jobs to those of materials scientists and physicists. All three fields explore the relationship between physical properties and functions, but inorganic chemistry is the most keenly focused on these properties at the molecular level.
Is a Creative Field
The field of inorganic chemistry has traditionally been characterized by scientists with an artistic or creative flair. Many inorganic chemists say that they were drawn to the field in part by the pretty colors of the metals in the lab and by the interesting things that could be done in the lab. They often say the opportunities for creativity and inferential thinking are what they like best about their work. Describing themselves as tinkerers, inorganic chemists like putting things together and solving problems and stress the importance of being detail oriented, precise, and persistent. Inorganic chemists describe their work as a constant challenge. "The job changes all the time," says Steve Caldwell, an inorganic chemist working at Dow Chemical. "Everyday there are a new set of issues and I have to determine which are the most important ones to work on first. It's definitely not a nine to five job."
Integrates Many Disciplines
Inorganic chemistry, like many scientific fields, is becoming more interdisciplinary. Breakthroughs are anticipated in the interface between fields rather than in the more traditional area. "In the future, jobs will not be filled by super specialists," says Sauer, "but by scientists with a broad base of knowledge." Even though a course of study like materials science or polymer science may appear to better position an individual for this interdisciplinary future, chemists in the field still strongly recommend getting a degree in inorganic chemistry. A degree in the basic discipline, will give a better understanding of bonding, valence, and orbital theory. In addition, students are advised to take courses outside inorganic chemistry both to prepare themselves to integrate knowledge towards problem solving as well as be flexible in today's tough job market. "Don't just stick to inorganic chemistry," Sauer says. "Learn inorganic chemistry and see how it applies in other areas." Caldwell adds, "Starting out in inorganic chemistry doesn't mean that's what you'll always do. I spent a few years doing environmental research; there are always applications in related fields."

Chemical Reaction - Chemical Energy

Chemical Reaction - Chemical Energy
Chemical reaction
Chemical reaction is a concept related to the transformation of a chemical substance through its interaction with another, or as a result of its interaction with some form of energy. A chemical reaction may occur naturally or carried out in a laboratory by chemists in specially designed vessels which are often laboratory glassware. It can result in the formation or dissociation of molecules, that is, molecules breaking apart to form two or more smaller molecules, or rearrangement of atoms within or across molecules. Chemical reactions usually involve the making or breaking of chemical bonds. Oxidation, reduction, dissociation, acid-base neutralization and molecular rearrangement are some of the commonly used kinds of chemical reactions.
A chemical reaction can be symbolically depicted through a chemical equation. While in a non-nuclear chemical reaction the number and kind of atoms on both sides of the equation are equal, for a nuclear reaction this holds true only for the nuclear particles viz. protons and neutrons.[40]
The sequence of steps in which the reorganization of chemical bonds may be taking place in the course of a chemical reaction is called its mechanism. A chemical reaction can be envisioned to take place in a number of steps, each of which may have a different speed. Many reaction intermediates with variable stability can thus be envisaged during the course of a reaction. Reaction mechanisms are proposed to explain the kinetics and the relative product mix of a reaction. Many physical chemists specialize in exploring and proposing the mechanisms of various chemical reactions. Several empirical rules, like the Woodward-Hoffmann rules often come handy while proposing a mechanism for a chemical reaction.
A stricter definition is that "a chemical reaction is a process that results in the interconversion of chemical species". Under this definition, a chemical reaction may be an elementary reaction or a stepwise reaction. An additional caveat is made, in that this definition includes cases where the interconversion of conformers is experimentally observable. Such detectable chemical reactions normally involve sets of molecular entities as indicated by this definition, but it is often conceptually convenient to use the term also for changes involving single molecular entities (i.e. 'microscopic chemical events').
Energy
In the context of chemistry, energy is an attribute of a substance as a consequence of its atomic, molecular or aggregate structure. Since a chemical transformation is accompanied by a change in one or more of these kinds of structure, it is invariably accompanied by an increase or decrease of energy of the substances involved. Some energy is transferred between the surroundings and the reactants of the reaction in the form of heat or light; thus the products of a reaction may have more or less energy than the reactants. A reaction is said to be exothermic if the final state is lower on the energy scale than the initial state; in the case of endothermic reactions the situation is otherwise.
Chemical reactions are invariably not possible unless the reactants surmount an energy barrier known as the activation energy. The speed of a chemical reaction (at given temperature T) is related to the activation energy E, by the Boltzmann's population factor e - E / kT - that is the probability of molecule to have energy greater than or equal to E at the given temperature T. This exponential dependence of a reaction rate on temperature is known as the Arrhenius equation. The activation energy necessary for a chemical reaction can be in the form of heat, light, electricity or mechanical force in the form of ultrasound.
A related concept free energy, which also incorporates entropy considerations, is a very useful means for predicting the feasibility of a reaction and determining the state of equilibrium of a chemical reaction, in chemical thermodynamics. A reaction is feasible only if the total change in the Gibbs free energy is negative, ; if it is equal to zero the chemical reaction is said to be at equilibrium.
There exist only limited possible states of energy for electrons, atoms and molecules. These are determined by the rules of quantum mechanics, which require quantization of energy of a bound system. The atoms/molecules in a higher energy state are said to be excited. The molecules/atoms of substance in an excited energy state are often much more reactive; that is, more amenable to chemical reactions.
The phase of a substance is invariably determined by its energy and the energy of its surroundings. When the intermolecular forces of a substance are such that the energy of the surroundings is not sufficient to overcome them, it occurs in a more ordered phase like liquid or solid as is the case with water (H2O); a liquid at room temperature because its molecules are bound by hydrogen bonds.[43] Whereas hydrogen sulfide (H2S) is a gas at room temperature and standard pressure, as its molecules are bound by weaker dipole-dipole interactions.
The transfer of energy from one chemical substance to another depends on the size of energy quanta emitted from one substance. However, heat energy is often transferred more easily from almost any substance to another because the phonons responsible for vibrational and rotational energy levels in a substance have much less energy than photons invoked for the electronic energy transfer. Thus, because vibrational and rotational energy levels are more closely spaced than electronic energy levels, heat is more easily transferred between substances relative to light or other forms of electronic energy. For example, ultraviolet electromagnetic radiation is not transferred with as much efficacy from one substance to another as thermal or electrical energy.
The existence of characteristic energy levels for different chemical substances is useful for their identification by the analysis of spectral lines. Different kinds of spectra are often used in chemical spectroscopy, e.g. IR, microwave, NMR, ESR, etc. Spectroscopy is also used to identify the composition of remote objects - like stars and distant galaxies - by analyzing their radiation spectra.
Emission spectrum of iron
The term chemical energy is often used to indicate the potential of a chemical substance to undergo a transformation through a chemical reaction or to transform other chemical substances.

Chemistry in Medicine ,Basic concepts Mole-Ions and salts-Acidity and basicity-Phase-Redox-Chemical bond

Chemistry in Medicine ,Basic concepts Mole-Ions and salts-Acidity and basicity-Phase-Redox-Chemical bond
Mole
A mole is the amount of a substance that contains as many elementary entities (atoms, molecules or ions) as there are atoms in 0.012 kilogram (or 12 grams) of carbon-12, where the carbon-12 atoms are unbound, at rest and in their ground state.[36] This number is known as the Avogadro constant, and is determined empirically. The currently accepted value is 6.02214179(30) × 1023 mol-1 (2007 CODATA). The best way to understand the meaning of the term "mole" is to compare it to terms such as dozen. Just as one dozen is equal to 12, one mole is equal to 6.02214179(30) × 1023. The term is used because it is much easier to say, for example, 1 mole of carbon atoms, than it is to say 6.02214179(30) × 1023 carbon atoms. Likewise, we can describe the number of entities as a multiple or fraction of 1 mole, e.g. 2 mole or 0.5 moles. Mole is an absolute number (having no units) and can describe any type of elementary object, although the mole's use is usually limited to measurement of subatomic, atomic, and molecular structures.The number of moles of a substance in one liter of a solution is known as its molarity. Molarity is the common unit used to express the concentration of a solution in physical chemistry.
Ions and salts
An ion is a charged species, an atom or a molecule, that has lost or gained one or more electrons. Positively charged cations (e.g. sodium cation Na+) and negatively charged anions (e.g. chloride Cl-) can form a crystalline lattice of neutral salts (e.g. sodium chloride NaCl). Examples of polyatomic ions that do not split up during acid-base reactions are hydroxide (OH-) and phosphate (PO43-).
Ions in the gaseous phase is often known as plasma.
Acidity and basicity
A substance can often be classified as an acid or a base. This is often done on the basis of a particular kind of reaction, namely the exchange of protons between chemical compounds. However, an extension to this mode of classification was brewed up by the American chemist, Gilbert Newton Lewis; in this mode of classification the reaction is not limited to those occurring in an aqueous solution, thus is no longer limited to solutions in water. According to concept as per Lewis, the crucial things being exchanged are charges[37]. There are several other ways in which a substance may be classified as an acid or a base, as is evident in the history of this concept
Phase
In addition to the specific chemical properties that distinguish different chemical classifications chemicals can exist in several phases. For the most part, the chemical classifications are independent of these bulk phase classifications; however, some more exotic phases are incompatible with certain chemical properties. A phase is a set of states of a chemical system that have similar bulk structural properties, over a range of conditions, such as pressure or temperature. Physical properties, such as density and refractive index tend to fall within values characteristic of the phase. The phase of matter is defined by the phase transition, which is when energy put into or taken out of the system goes into rearranging the structure of the system, instead of changing the bulk conditions.
Sometimes the distinction between phases can be continuous instead of having a discrete boundary, in this case the matter is considered to be in a supercritical state. When three states meet based on the conditions, it is known as a triple point and since this is invariant, it is a convenient way to define a set of conditions.
The most familiar examples of phases are solids, liquids, and gases. Many substances exhibit multiple solid phases. For example, there are three phases of solid iron (alpha, gamma, and delta) that vary based on temperature and pressure. A principal difference between solid phases is the crystal structure, or arrangement, of the atoms. Less familiar phases include plasmas, Bose-Einstein condensates and fermionic condensates and the paramagnetic and ferromagnetic phases of magnetic materials. While most familiar phases deal with three-dimensional systems, it is also possible to define analogs in two-dimensional systems, which has received attention for its relevance to systems in biology.
Redox
It is a concept related to the ability of atoms of various substances to lose or gain electrons. Substances that have the ability to oxidize other substances are said to be oxidative and are known as oxidizing agents, oxidants or oxidizers. An oxidant removes electrons from another substance. Similarly, substances that have the ability to reduce other substances are said to be reductive and are known as reducing agents, reductants, or reducers. A reductant transfers electrons to another substance, and is thus oxidized itself. And because it "donates" electrons it is also called an electron donor. Oxidation and reduction properly refer to a change in oxidation number—the actual transfer of electrons may never occur. Thus, oxidation is better defined as an increase in oxidation number, and reduction as a decrease in oxidation number.
Chemical bond
Electron atomic and molecular orbitals
A chemical bond is a concept for understanding how atoms stick together in molecules. It may be visualized as the multipole balance between the positive charges in the nuclei and the negative charges oscillating about them.[39] More than simple attraction and repulsion, the energies and distributions characterize the availability of an electron to bond to another atom. These potentials create the interactions which hold atoms together in molecules or crystals. In many simple compounds, Valence Bond Theory, the Valence Shell Electron Pair Repulsion model (VSEPR), and the concept of oxidation number can be used to predict molecular structure and composition. Similarly, theories from classical physics can be used to predict many ionic structures. With more complicated compounds, such as metal complexes, valence bond theory fails and alternative approaches, primarily based on principles of quantum chemistry such as the molecular orbital theory, are necessary. See diagram on electronic orbitals.

Chemistry in Medicine ,Basic concepts Atom, Chemical Element-Compound-Substance-Molecule

Chemistry in Medicine ,Basic concepts Atom, Chemical Element-Compound-Substance-Molecule

Atom
Main article: Atom
An atom is the basic unit of chemistry. It consists of a positively charged core (the atomic nucleus) which contains protons and neutrons, and which maintains a number of electrons to balance the positive charge in the nucleus. The atom is also the smallest entity that can be envisaged to retain some of the chemical properties of the element, such as electronegativity, ionization potential, preferred oxidation state(s), coordination number, and preferred types of bonds to form (e.g., metallic, ionic, covalent).
Element
Main article: Chemical element
The concept of chemical element is related to that of chemical substance. A chemical element is characterized by a particular number of protons in the nuclei of its atoms. This number is known as the atomic number of the element. For example, all atoms with 6 protons in their nuclei are atoms of the chemical element carbon, and all atoms with 92 protons in their nuclei are atoms of the element uranium. However, several isotopes of an element, that differ from one another in the number of neutrons present in the nucleus, may exist.
The most convenient presentation of the chemical elements is in the periodic table of the chemical elements, which groups elements by atomic number. Due to its ingenious arrangement, groups, or columns, and periods, or rows, of elements in the table either share several chemical properties, or follow a certain trend in characteristics such as atomic radius, electronegativity, etc. Lists of the elements by name, by symbol, and by atomic number are also available.
Compound
Main article: Chemical compound
A compound is a substance with a particular ratio of atoms of particular chemical elements which determines its composition, and a particular organization which determines chemical properties. For example, water is a compound containing hydrogen and oxygen in the ratio of two to one, with the oxygen atom between the two hydrogen atoms, and an angle of 104.5° between them. Compounds are formed and interconverted by chemical reactions.
Substance
Main article: Chemical substance
A chemical substance is a kind of matter with a definite composition and set of properties.[33] Strictly speaking, a mixture of compounds, elements or compounds and elements is not a chemical substance, but it may be called a chemical. Most of the substances we encounter in our daily life are some kind of mixture; for example: air, alloys, biomass, etc.
Nomenclature of substances is a critical part of the language of chemistry. Generally it refers to a system for naming chemical compounds. Earlier in the history of chemistry substances were given name by their discoverer, which often led to some confusion and difficulty. However, today the IUPAC system of chemical nomenclature allows chemists to specify by name specific compounds amongst the infinite variety of possible chemicals. The standard nomenclature of chemical substances is set by the International Union of Pure and Applied Chemistry (IUPAC). There are well-defined systems in place for naming chemical species. Organic compounds are named according to the organic nomenclature system.[34] Inorganic compounds are named according to the inorganic nomenclature system.[35] In addition the Chemical Abstracts Service has devised a method to index chemical substance. In this scheme each chemical substance is identifiable by a numeric number known as CAS registry number.
Molecule
Main article: Molecule
A molecule is the smallest indivisible portion, besides an atom, of a pure chemical substance that has its unique set of chemical properties, that is, its potential to undergo a certain set of chemical reactions with other substances. Molecules can exist as electrically neutral units unlike ions. Molecules are typically a set of atoms bound together by covalent bonds, such that the structure is electrically neutral and all valence electrons are paired with other electrons either in bonds or in lone pairs.A molecular structure depicts the bonds and relative positions of atoms in a molecule such as that in Paclitaxel shown hereOne of the main characteristic of a molecule is its geometry often called its structure. While the structure of diatomic, triatomic or tetra atomic molecules may be trivial, (linear, angular pyramidal etc.) the structure of polyatomic molecules, that are constituted of more than six atoms (of several elements) can be crucial for its chemical nature.

Use of inorganic Chemistry in Medicine. Introduction-History-Etymology-Definitions

Use of inorganic Chemistry in Medicine.  Introduction-History-Etymology-Definitions           

Introduction
Chemistry is an integral part of the science curriculum both at the high school as well as the early college level. At these levels, it is often called "general chemistry" which is an introduction to a wide variety of fundamental concepts that enable the student to acquire tools and skills useful at the advanced levels, whereby chemistry is invariably studied in any of its various sub-disciplines. Scientists, engaged in chemical research are known as chemists. Most chemists specialize in one or more sub-disciplines. Chemistry is the scientific study of interaction of chemical substances that are constituted of atoms or the subatomic particles: protons, electrons and neutrons. Atoms combine to produce molecules or crystals. Chemistry is often called "the central science" because it connects the other natural sciences such as astronomy, physics, material science, biology, and geology
The genesis of chemistry can be traced to certain practices, known as alchemy, which had been practiced for several millennia in various parts of the world, particularly the Middle East.
The structure of objects we commonly use and the properties of the matter we commonly interact with, are a consequence of the properties of chemical substances and their interactions. For example, steel is harder than iron because its atoms are bound together in a more rigid crystalline lattice; wood burns or undergoes rapid oxidation because it can react spontaneously with oxygen in a chemical reaction above a certain temperature; sugar and salt dissolve in water because their molecular/ionic properties are such that dissolution is preferred under the ambient conditions.
The transformations that are studied in chemistry are a result of interaction either between different chemical substances or between matter and energy. Traditional chemistry involves study of interactions between substances in a chemistry laboratory using various forms of laboratory glassware.
A chemical reaction is a transformation of some substances into one or more other substances. It can be symbolically depicted through a chemical equation. The number of atoms on the left and the right in the equation for a chemical transformation is most often equal. The nature of chemical reactions a substance may undergo and the energy changes that may accompany it are constrained by certain basic rules, known as chemical laws.
Energy and entropy considerations are invariably important in almost all chemical studies. Chemical substances are classified in terms of their structure, phase as well as their chemical compositions. They can be analysed using the tools of chemical analysis, e.g. spectroscopy and chromatography.
History
Ancient Egyptians pioneered the art of synthetic "wet" chemistry up to 4,000 years ago. By 1000 BC ancient civilizations were using technologies that formed the basis of the various branches of chemistry such as; extracting metal from their ores, making pottery and glazes, fermenting beer and wine, making pigments for cosmetics and painting, extracting chemicals from plants for medicine and perfume, making cheese, dying cloth, tanning leather, rendering fat into soap, making glass, and making alloys like bronze.
The genesis of chemistry can be traced to the widely observed phenomenon of burning that led to metallurgy- the art and science of processing ores to get metals (e.g. metallurgy in ancient India). The greed for gold led to the discovery of the process for its purification, even though the underlying principles were not well understood -- it was thought to be a transformation rather than purification. Many scholars in those days thought it reasonable to believe that there exist means for transforming cheaper (base) metals into gold. This gave way to alchemy and the search for the Philosopher's Stone which was believed to bring about such a transformation by mere touch.
Greek atomism dates back to 440 BC, as what might be indicated by the book De Rerum Natura (The Nature of Things) written by the Roman Lucretius in 50 BC. Much of the early development of purification methods is described by Pliny the Elder in his Naturalis Historia.
Some consider medieval Arabs and Persians to be the earliest chemists, who introduced precise observation and controlled experimentation into the field, and discovered numerous chemical substances. The most influential Muslim chemists were Geber (d. 815), al-Kindi (d. 873), al-Razi (d. 925), and al-Biruni (d. 1048). The works of Geber became more widely known in Europe through Latin translations by a pseudo-Geber in 14th century Spain, who also wrote some of his own books under the pen name "Geber". The contribution of Indian alchemists and metallurgists in the development of chemistry was also quite significant.[16]
The emergence of chemistry in Europe was primarily due to the recurrent incidence of the plague and blights there during the so called Dark Ages. This gave rise to a need for medicines. It was thought that there exists a universal medicine called the Elixir of Life that can cure all diseases, but like the Philosopher's Stone, it was never found.
For some practitioners, alchemy was an intellectual pursuit, over time, they got better at it. Paracelsus (1493-1541), for example, rejected the 4-elemental theory and with only a vague understanding of his chemicals and medicines, formed a hybrid of alchemy and science in what was to be called iatrochemistry. Similarly, the influences of philosophers such as Sir Francis Bacon (1561-1626) and René Descartes (1596-1650), who demanded more rigor in mathematics and in removing bias from scientific observations, led to a scientific revolution. In chemistry, this began with Robert Boyle (1627-1691), who came up with an equation known as Boyle's Law about the characteristics of gaseous state.[17] Chemistry indeed came of age when Antoine Lavoisier (1743-1794), developed the theory of Conservation of mass in 1783; and the development of the Atomic Theory by John Dalton around 1800. The Law of Conservation of Mass resulted in the reformulation of chemistry based on this law and the oxygen theory of combustion, which was largely based on the work of Lavoisier. Lavoisier's fundamental contributions to chemistry were a result of a conscious effort to fit all experiments into the framework of a single theory. He established the consistent use of the chemical balance, used oxygen to overthrow the phlogiston theory, and developed a new system of chemical nomenclature and made contribution to the modern metric system. Lavoisier also worked to translate the archaic and technical language of chemistry into something that could be easily understood by the largely uneducated masses, leading to an increased public interest in chemistry. All these advances in chemistry led to what is usually called the chemical revolution. The contributions of Lavoisier led to what is now called modern chemistry - the chemistry that is studied in educational institutions all over the world. It is because of these and other contributions that Antoine Lavoisier is often celebrated as the "Father of Modern Chemistry". The later discovery of Friedrich Wöhler that many natural substances, organic compounds, can indeed be synthesized in a chemistry laboratory also helped the modern chemistry to mature from its infancy.
The discoveries of the chemical elements has a long history from the days of alchemy and culminating in the creation of the periodic table of the chemical elements by Dmitri Mendeleev (1834-1907) and later discoveries of some synthetic elements.
Etymology
The word chemistry comes from the earlier study of alchemy, which is a pseudoscientific practice which encompasses elements of chemistry, metallurgy, philosophy, astrology, astronomy, mysticism and medicine. Alchemy is commonly thought of as the quest to turn lead or another common starting material into gold. As to the origin of the word "alchemy" the question is a debatable one; it certainly can be traced back to the Greeks, and some, following E. Wallis Budge, have also asserted Egyptian origins. Many believe that the word "alchemy" is derived from the word Chemi or Kimi, which is the name of Egypt in Egyptian. The word was subsequently borrowed by the Greeks, and from the Greeks by the Arabs when they occupied Alexandria (Egypt) in the 7th century. The Arabs added the Arabic definite article "al" to the word, resulting in the word ???????? "al-kimiya", from which is derived the old French alkemie. A tentative outline is as follows:
1. Egyptian alchemy [3,000 BCE – 400 BCE], formulate early "element" theories such as the Ogdoad.
2. Greek alchemy [332 BCE – 642 CE], the Greek king Alexander the Great conquers Egypt and founds Alexandria, having the world's largest library, where scholars and wise men gather to study.
3. Arab alchemy [642 CE – 1200], the Arabs invade Alexandria; Jabir is the main chemist
4. European alchemy [1300 – present], Pseudo-Geber builds on Arabic chemistry
5. Chemistry [1661], Boyle writes his classic chemistry text The Sceptical Chymist
6. Chemistry [1787], Lavoisier writes his classic Elements of Chemistry
7. Chemistry [1803], Dalton publishes his Atomic Theory
Thus, an alchemist was called a 'chemist' in popular speech, and later the suffix "-ry" was added to this to describe the art of the chemist as "chemistry".
Definitions
In retrospect, the definition of chemistry seems to invariably change per decade, as new discoveries and theories add to the functionality of the science. Shown below are some of the standard definitions used by various noted chemists:
• Alchemy (330) – the study of the composition of waters, movement, growth, embodying, disembodying, drawing the spirits from bodies and bonding the spirits within bodies (Zosimos).
• Chymistry (1661) – the subject of the material principles of mixt bodies (Boyle).[26]
• Chymistry (1663) – a scientific art, by which one learns to dissolve bodies, and draw from them the different substances on their composition, and how to unite them again, and exalt them to a higher perfection (Glaser).
• Chemistry (1730) – the art of resolving mixt, compound, or aggregate bodies into their principles; and of composing such bodies from those principles (Stahl).
• Chemistry (1837) – the science concerned with the laws and effects of molecular forces (Dumas.
• Chemistry (1947) – the science of substances: their structure, their properties, and the reactions that change them into other substances (Pauling).
• Chemistry (1998) – the study of matter and the changes it undergoes (Chang).