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Escherichia coli K-12 substr. MG1655 Pathway: 8-amino-7-oxononanoate biosynthesis I

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Locations of Mapped Genes:

Genetic Regulation Schematic: ?

Synonyms: 7-keto-8-aminopelargonate biosynthesis I

Superclasses: Biosynthesis Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis Vitamins Biosynthesis Biotin Biosynthesis 7-Keto,8-aminopelargonate Biosynthesis

Summary:
Biotin is an essential cofactor for carboxyl group transfer enzymes such as acetyl-CoA carboxylase, and is required by all forms of life [Neidhardt96].

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 [Lin10].

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 [Lin10] 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 [Lin12a]. 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.

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 [Lin10].

Superpathways: biotin biosynthesis I

Credits:
Created 17-Aug-2010 by Caspi R , SRI International


References

Cleary72: Cleary PP, Campbell A (1972). "Deletion and complementation analysis of biotin gene cluster of Escherichia coli." J Bacteriol 112(2);830-9. PMID: 4563978

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

Lemoine96: Lemoine Y, Wach A, Jeltsch JM (1996). "To be free or not: the fate of pimelate in Bacillus sphaericus and in Escherichia coli." Mol Microbiol 19(3);645-7. PMID: 8830257

Lezius63: Lezius A, Ringelmann E, Lynen F (1963). "[On the biochemical function of biotin. IV. The biosynthesis of biotin.]." Biochem Z 336;510-25. PMID: 13930373

Lin10: Lin S, Hanson RE, Cronan JE (2010). "Biotin synthesis begins by hijacking the fatty acid synthetic pathway." Nat Chem Biol 6(9);682-8. PMID: 20693992

Lin12a: Lin S, Cronan JE (2012). "The BioC O-Methyltransferase Catalyzes Methyl Esterification of Malonyl-Acyl Carrier Protein, an Essential Step in Biotin Synthesis." J Biol Chem. PMID: 22965231

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.

Rolfe68: Rolfe B, Eisenberg MA (1968). "Genetic and biochemical analysis of the biotin loci of Escherichia coli K-12." J Bacteriol 96(2);515-24. PMID: 4877129

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.

Webb07: Webb, M.E., Marquet, A., Mendel, R.R., Rebeille, F., Smith, A.G (2007). "Elucidating biosynthetic pathways for vitamins and cofactors." Nat. Prod. Rep. 24:988-1008.

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

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

Bergler92: Bergler H, Hogenauer G, Turnowsky F (1992). "Sequences of the envM gene and of two mutated alleles in Escherichia coli." J Gen Microbiol 1992;138 ( Pt 10);2093-100. PMID: 1364817

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

Binkowski05: Binkowski TA, Joachimiak A, Liang J (2005). "Protein surface analysis for function annotation in high-throughput structural genomics pipeline." Protein Sci 14(12);2972-81. PMID: 16322579

Byers07: Byers DM, Gong H (2007). "Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family." Biochem Cell Biol 85(6);649-62. PMID: 18059524

Campbell01a: Campbell JW, Cronan JE (2001). "Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery." Annu Rev Microbiol 55;305-32. PMID: 11544358

Cao10: Cao Y, Yang J, Xian M, Xu X, Liu W (2010). "Increasing unsaturated fatty acid contents in Escherichia coli by coexpression of three different genes." Appl Microbiol Biotechnol 87(1);271-80. PMID: 20135119

Chan10: Chan DI, Vogel HJ (2010). "Current understanding of fatty acid biosynthesis and the acyl carrier protein." Biochem J 430(1);1-19. PMID: 20662770

Del67: Del Campillo-Campbell A, Kayajanian G, Campbell A, Adhya S (1967). "Biotin-requiring mutants of Escherichia coli K-12." J Bacteriol 94(6);2065-6. PMID: 4864413

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

ECOSAL: "Escherichia coli and Salmonella: Cellular and Molecular Biology." Online edition.

Escaich11: Escaich S, Prouvensier L, Saccomani M, Durant L, Oxoby M, Gerusz V, Moreau F, Vongsouthi V, Maher K, Morrissey I, Soulama-Mouze C (2011). "The MUT056399 inhibitor of FabI is a new antistaphylococcal compound." Antimicrob Agents Chemother 55(10);4692-7. PMID: 21825292

Feng09: Feng Y, Cronan JE (2009). "Escherichia coli unsaturated fatty acid synthesis: complex transcription of the fabA gene and in vivo identification of the essential reaction catalyzed by FabB." J Biol Chem 284(43);29526-35. PMID: 19679654

Garwin80: Garwin JL, Klages AL, Cronan JE (1980). "Structural, enzymatic, and genetic studies of beta-ketoacyl-acyl carrier protein synthases I and II of Escherichia coli." J Biol Chem 1980;255(24);11949-56. PMID: 7002930

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA01a: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

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Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
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