If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
Synonyms: vitamin H biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Biotin Biosynthesis|
Despite the importance and prevalance of biotin, its detailed biosynthetic pathway remained enigmatic for over 70 years. The first complete pathway for biotin synthesis was suggested for its synthesis in E. coli [Lin10a].
Biotin consists of two fused heterocyclic rings and a pentanoate side chain, derived from a pimelate-like structure. The early steps of the pathway, which are described here, describe the synthesis of the precursor of the pimelate moiety. The late steps of the pathway, which are responsible for forming the two rings in the structure of biotin, are described in biotin biosynthesis from 8-amino-7-oxononanoate I.
The origins of the biotin carbon atoms in E. coli are known from 13C NMR analysis of products labeled in vivo [Ifuku94, Sanyal94]. The C3, C5 and C7 carbons are derived from carbon C1 of acetate, while the C2, C4 and C6 carbons are derived from carbon C2 of acetate. The C1 carbon originates from CO2. This labeling pattern indicated that the pimeloyl moiety of biotin is formed by head-to-tail incorporation of three intact acetate units, similar to the synthesis of fatty acids [Sanyal94]. As the biotin C1 and C7 atoms show different labeling patterns, free pimelic acid (a symmetrical molecule) could not be an intermediate, and thus it has been assumed that pimeloyl-CoA is the precursor [Webb07].
The elucidation of the pathway proved difficult, mostly since only two genes, bioC and bioH, were implicated in the synthesis of the pimeloyl moiety [Cleary72, Lemoine96, Rolfe68]. Based on these finding, there have been several suggestions that enzymes of the fatty acid biosynthesis pathway are involved, although none of these suggestions could explain the full process [Sanyal94, Lezius63]. An inclusive model was finally suggested in 2010 [Lin10a] and later refined. Based on this model, BioC converts the free carboxyl group of a malonyl-[acp] to its methyl ester by transfer of a methyl group from S-adenosyl-L-methionine [Lin12b]. The newly acquired methyl group mimics the methyl ends of normal fatty acyl chains, and enables the esterified a malonyl-[acp] methyl ester to enter the fatty acid synthetic pathway.
Two reiterations of the fatty acid elongation cycle (see fatty acid elongation -- saturated) produce pimeloyl-[acp] methyl ester, which is cleaved by BioH to give pimeloyl-[acp]. The [acp] protein is then removed in a complex reaction catalyzed by BioF, forming 8-amino-7-oxononanoate, the first intermediate in biotin ring assembly.
The next step in the pathway involves the unusual use of the common methyl-group donor S-adenosyl-L-methionine as an amino-group donor, a reaction catalyzed by 7,8-diaminopelargonic acid synthase [Stoner75a, Stoner75, Eliot02]. The product of this reaction, 7,8-diaminopelargonate, is the target of a unique carboxylase, dethiobiotin synthetase. This enzyme catalyzes the first ring closure by a carboxylation reaction that does not require biotin as a prosthetic group, forming dethiobiotin [Krell70].
The ultimate step in the pathway is catalyzed by biotin synthase. This enzyme inserts a sulfur atom between C6 and C9 of dethiobiotin in a S-adenosyl-L-methionine-dependent reaction. It has not been possible to reconstitute a catalytic reaction of this enzyme in vitro, and there is some uncertainty regarding the reaction mechanism, cofactor requirements, and the source of the sulfur atom [Jarrett05]. However, recent experiments have suggested that a a [2Fe-2S] iron-sulfur cluster of the enzyme is the source of the sulfur atom. Consistent with its proposed role as the sulfur donor, degradation of the [2Fe-2S] cluster [Jameson04] as well as exchange of sulfur atoms between the [2Fe-2S] and [4Fe-4S] clusters [Tse06] is observed during turnover of the enzyme.
According to this model, the introduction of the methyl ester early in the pathway disguises the biotin synthetic intermediates so that they become substrates for the fatty acid synthetic pathway. When the synthesis of the pimeloyl moiety is complete and disguise is no longer needed, the methyl group is removed to free the carboxyl group that will eventually be used to attach biotin to its target metabolic enzymes.
An in vitro system that uses dialyzed cell extracts was used in combination with several mutant strains and purified proteins to verify the proposed pathway [Lin10a].
Eliot02: Eliot AC, Sandmark J, Schneider G, Kirsch JF (2002). "The dual-specific active site of 7,8-diaminopelargonic acid synthase and the effect of the R391A mutation." Biochemistry 41(42);12582-9. PMID: 12379100
Ifuku94: Ifuku O, Miyaoka H, Koga N, Kishimoto J, Haze S, Wachi Y, Kajiwara M (1994). "Origin of carbon atoms of biotin. 13C-NMR studies on biotin biosynthesis in Escherichia coli." Eur J Biochem 220(2);585-91. PMID: 8125118
Neidhardt96: Neidhardt FC, Curtiss III R, Ingraham JL, Lin ECC, Low Jr KB, Magasanik B, Reznikoff WS, Riley M, Schaechter M, Umbarger HE "Escherichia coli and Salmonella, Cellular and Molecular Biology, Second Edition." American Society for Microbiology, Washington, D.C., 1996.
Park06: Park YJ, Yoo CB, Choi SY, Lee HB (2006). "Purifications and characterizations of a ferredoxin and its related 2-oxoacid:ferredoxin oxidoreductase from the hyperthermophilic archaeon, Sulfolobus solfataricus P1." J Biochem Mol Biol 39(1);46-54. PMID: 16466637
Sanyal94: Sanyal, I, Lee, SL, Flint, DH (1994). "Biosynthesis of pimeloyl-CoA, a biotin precursor in Escherichia coli, follows a modified fatty acid synthesis pathway: 13C-labeling studies." J. Am. Chem. Soc. 116(6):2637-2638.
Stoner75: Stoner GL, Eisenberg MA (1975). "Biosynthesis of 7, 8-diaminopelargonic acid from 7-keto-8-aminopelargonic acid and S-adenosyl-L-methionine. The kinetics of the reaction." J Biol Chem 1975;250(11);4037-43. PMID: 1092682
Tse06: Tse Sum Bui B, Mattioli TA, Florentin D, Bolbach G, Marquet A (2006). "Escherichia coli biotin synthase produces selenobiotin. Further evidence of the involvement of the [2Fe-2S]2+ cluster in the sulfur insertion step." Biochemistry 45(11);3824-34. PMID: 16533066
AbdelHamid07: Abdel-Hamid AM, Cronan JE (2007). "In vivo resolution of conflicting in vitro results: synthesis of biotin from dethiobiotin does not require pyridoxal phosphate." Chem Biol 14(11);1215-20. PMID: 18022560
Agarwal12a: Agarwal V, Lin S, Lukk T, Nair SK, Cronan JE (2012). "Structure of the enzyme-acyl carrier protein (ACP) substrate gatekeeper complex required for biotin synthesis." Proc Natl Acad Sci U S A 109(43);17406-11. PMID: 23045647
Alexeev94: Alexeev D, Bury SM, Boys CW, Turner MA, Sawyer L, Ramsey AJ, Baxter HC, Baxter RL (1994). "Sequence and crystallization of Escherichia coli dethiobiotin synthetase, the penultimate enzyme of biotin biosynthesis." J Mol Biol 1994;235(2);774-6. PMID: 8289297
Alexeev98: Alexeev D, Alexeeva M, Baxter RL, Campopiano DJ, Webster SP, Sawyer L (1998). "The crystal structure of 8-amino-7-oxononanoate synthase: a bacterial PLP-dependent, acyl-CoA-condensing enzyme." J Mol Biol 1998;284(2);401-19. PMID: 9813126
Baldock96: Baldock C, Rafferty JB, Sedelnikova SE, Baker PJ, Stuitje AR, Slabas AR, Hawkes TR, Rice DW (1996). "A mechanism of drug action revealed by structural studies of enoyl reductase." Science 274(5295);2107-10. PMID: 8953047
Baxter94: Baxter RL, Ramsey AJ, McIver LA, Baxter HC (1994). "Mechanism of Dethiobiotin Synthetase -- Characterisation of the 8-Aminocarbamate of (7R,8S)-7,8 Diaminononanoate as an Enzyme-bound Intermediate." J Chem Soc Chem Comm (1994);559-560.
Benda02: Benda R, Tse Sum Bui B, Schunemann V, Florentin D, Marquet A, Trautwein AX (2002). "Iron-sulfur clusters of biotin synthase in vivo: a Mossbauer study." Biochemistry 41(50);15000-6. PMID: 12475249
Bergler94: Bergler H, Wallner P, Ebeling A, Leitinger B, Fuchsbichler S, Aschauer H, Kollenz G, Hogenauer G, Turnowsky F (1994). "Protein EnvM is the NADH-dependent enoyl-ACP reductase (FabI) of Escherichia coli." J Biol Chem 1994;269(8);5493-6. PMID: 8119879
Bergler96: Bergler H, Fuchsbichler S, Hogenauer G, Turnowsky F (1996). "The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA." Eur J Biochem 242(3);689-94. PMID: 9022698
Berkovitch04: Berkovitch F, Nicolet Y, Wan JT, Jarrett JT, Drennan CL (2004). "Crystal structure of biotin synthase, an S-adenosylmethionine-dependent radical enzyme." Science 303(5654);76-9. PMID: 14704425
Breen03: Breen RS, Campopiano DJ, Webster S, Brunton M, Watt R, Baxter RL (2003). "The mechanism of 7,8-diaminopelargonate synthase; the role of S-adenosylmethionine as the amino donor." Org Biomol Chem 1(20);3498-9. PMID: 14599009
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