Heme, biosynthesis structure

Heat of combustion, 113 Heat of hydrogenation, 186 table of, 187 Heat of reaction, 154 Helicase, DNA replication and, 1106 Hell-Volhard-Zelinskii reaction, 849 amino acid synthesis and. 1025 mechanism of, 849 Heme, biosynthesis of, 966 structure of, 946 Hemiacetal, 717 Hemiketal, 717 Hemithioacetal, 1148 Henderson-Hasselbalch equation,... 

Many photobleaching herbicides act by inhibiting the enzyme protoporphyrinogen oxidase (Protox), which catalyzes the last step in common between chlorophyll and heme biosynthesis. Usnic acid shares some structural features in common with these herbicides, such as the diphenyl ether scaffolding. The inhibitory activity of (-)-usnic acid on Protox was similar to that of the herbicide, acifluorfen, (I50 ca. 3 pM). However, these compounds did not displace acifluorfen from its binding site on Protox (data not shown), indicating that this natural product interacts with Protox differently than other photobleaching inhibitors. 

Here we limit ourselves to an example of a 4Fe-4S center from the radical 5 -adenosyl-L-methioiiine (SAM) enzyme oxygen-independent coproporphyrinogen III oxidase HemN. This enzyme catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX dming bacterial heme biosynthesis. The crystal structure of Escherichia coli HemN revealed the presence of an unusually coordinated iron-sulfur cluster and two molecules of SAM. 

Astner 1, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW. Crystal structure of 5-aminolevuhnate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans. EMBO J. 2005 24 3166-3177. 

The genes for all the enzymes of human heme biosynthesis have been characterized (Table 32-2), and the structures of 5-aminolevulinic acid dehydratase (ALAD), hydroxymethyl-bilane synthase (HMBS), uroporphyrinogen-III synthase (UROS), uroporphyrinogen decarboxylase (UROD), and ferrochelatase (FECH) have been determined by x-ray crys-tallography. - - ... 

Wu CK, Dailey HA, Rose JP, Burden A, Sellers VM> Wang BC. The 2.0 A structure of human fer-rochelatase, the terminal enzyme of heme biosynthesis. Nat Struct Biol 2000 8 156-160. 

We devised a screen for isolating mutants defective in iron-dependent regulation of heme biosynthesis that did not require prior knowledge of the mechanism or of the rate-limiting steps [83]. We speculated that if the pathway as a whole were regulated by iron, a mutant defective in that control would accumulate protoporphyrin under iron limitation. Mutants defective in the heme synthesis enzymes ferrochelatase [75] or protoporphyrinogen oxidase would likely have a similar phenotype, but porphyrin accumulation would likely be independent of iron in the structural gene mutants, and those strains would also be expected to be heme auxotrophs. 

Frataxin (Figure 2) has recently been identified as a likely physiological iron donor to ISU during assembly of the [2Fe-2S] cluster core 10, 21-23), and to ferrochelatase for the final step of heme biosynthesis 24, 25), Dysfunction of fi-ataxin results in mitochondrial iron accumulation and oxidative damage to mitochondrial DNA 26, 27), as well as the potential to disrupt other cellular processes dependent on such iron cofactors. This is the first characterized example of an iron-delivery protein and it remains to be seen how relevant its functional chemistry will be, relative to cell metabolism across a spectrum of organisms. As noted later, the absence of sequence homologs in certain other organisms does not preclude the presence of structural and functional... 

Protoporphyrin IX is a precursor for the biosynthesis of heme, chlorophyll, and cytochrome. Bile pigment is also derived from heme. The structure of bilirubin, the main component of this bile pigment, is shown [7]. Bilirubin is also a main component of the crude drug Go-Oh (bezoar, concave) prepared from the unhealthy calculus in the gallbladder or bile duct of cattle. Bezoar is an animal preparation used for detoxification, as an antipyretic, and as a cardiotonic. The biosynthesis of chlorophylls and bacte-riochlorophylls from protoporphyrin IX has been reviewed [8]. 

The similarity between the structures of the corrinoids and the porphyrins becomes evident from comparison of cobyrinic acid (75) (the simplest of the corronoids so far isolated) with uroporphyrinogen III (70). The possibility of a biosynthetic relationship between these structures was suggested by Shemin, who reported the incorporation of [14C]ALA into vitamin Bn and confirmed by the subsequent demonstration that PBG was also incorporated. The ubiquitous precursorial role of uroporphyrinogen III in heme, chlorophyll and corrinoid biosynthesis proposed by Porra (65BBA(107)176) was, however, not substantiated by experimental evidence until much later, when under carefully controlled conditions cells of Propionibacterium shermanii were shown to incorporate radioactivity from [14C]uroporphyrinogen III into vitamin Bn (72JA8269). 

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