The Enzyme Database

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EC 2.3.1.261     
Accepted name: (4-hydroxyphenyl)alkanoate synthase
Reaction: (1) 4-hydroxybenzoyl-[(4-hydroxyphenyl)alkanoate synthase] + 8 malonyl-CoA + 16 NADPH + 16 H+ = 17-(4-hydroxyphenyl)heptadecanoyl-[(4-hydroxyphenyl)alkanoate synthase] + 8 CO2 + 8 CoA + 16 NADP+ + 8 H2O
(2) 4-hydroxybenzoyl-[(4-hydroxyphenyl)alkanoate synthase] + 9 malonyl-CoA + 18 NADPH + 18 H+ + holo-[(4-hydroxyphenyl)alkanoate synthase] = 19-(4-hydroxyphenyl)nonadecanoyl-[(4-hydroxyphenyl)alkanoate synthase] + 9 CO2 + 9 CoA + 18 NADP+ + 9 H2O
Other name(s): msl7 (gene name); Pks15/1
Systematic name: malonyl-CoA:4-hydroxybenzoyl-[(4-hydroxyphenyl)alkanoate synthase] malonyltransferase [(4-hydroxyphenyl)alkanoate-forming]
Comments: The enzyme is part of the biosynthetic pathway of phenolphthiocerol, a lipid that serves as a virulence factor of pathogenic mycobacteria. It catalyses the elongation of 4-hydroxybenzoate that is loaded on its acyl-carrier domain to form (4-hydroxyphenyl)alkanoate intermediates. The enzyme adds either 8 or 9 malonyl-CoA units, resulting in formation of 17-(4-hydroxyphenyl)heptadecanoate or 19-(4-hydroxyphenyl)nonadecanoate, respectively. As the enzyme lacks a thioesterase domain [1], the product remains loaded on the acyl-carrier domain at the end of catalysis, and has to be hydrolysed by an as-yet unknown mechanism.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Sirakova, T.D., Thirumala, A.K., Dubey, V.S., Sprecher, H. and Kolattukudy, P.E. The Mycobacterium tuberculosis pks2 gene encodes the synthase for the hepta- and octamethyl-branched fatty acids required for sulfolipid synthesis. J. Biol. Chem. 276 (2001) 16833–16839. [DOI] [PMID: 11278910]
2.  Constant, P., Perez, E., Malaga, W., Laneelle, M.A., Saurel, O., Daffe, M. and Guilhot, C. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem. 277 (2002) 38148–38158. [DOI] [PMID: 12138124]
3.  Simeone, R., Leger, M., Constant, P., Malaga, W., Marrakchi, H., Daffe, M., Guilhot, C. and Chalut, C. Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J. 277 (2010) 2715–2725. [DOI] [PMID: 20553505]
[EC 2.3.1.261 created 2017]
 
 
EC 2.3.1.282     
Accepted name: phenolphthiocerol/phthiocerol/phthiodiolone dimycocerosyl transferase
Reaction: (1) 2 a mycocerosyl-[mycocerosic acid synthase] + a phthiocerol = a dimycocerosyl phthiocerol + 2 holo-[mycocerosic acid synthase]
(2) 2 a mycocerosyl-[mycocerosic acid synthase] + a phthiodiolone = a dimycocerosyl phthiodiolone + 2 holo-[mycocerosic acid synthase]
(3) 2 a mycocerosyl-[mycocerosic acid synthase] + a phenolphthiocerol = a dimycocerosyl phenolphthiocerol + 2 holo-[mycocerosic acid synthase]
Glossary: a mycocerosate = 2,4,6-trimethyl- and 2,4,6,8-tetramethyl-2-alkanoic acids present in many pathogenic mycobacteria. The chiral centers bearing the methyl groups have an L (levorotatory) stereo configuration.
a phthiocerol = a linear carbohydrate molecule to which one methoxyl group, one methyl group, and two secondary hydroxyl groups are attached.
a phthiodiolone = an intermediate in phthiocerol biosynthesis, containing an oxo group where phthiocerols contain a methoxyl group
a phenolphthiocerol = a compound related to phthiocerol that contains a phenol group at the ω end of the molecule
Other name(s): papA5 (gene name)
Systematic name: mycocerosyl-[mycocerosic acid synthase]:phenolphthiocerol/phthiocerol/phthiodiolone dimycocerosyl transferase
Comments: The enzyme, present in certain pathogenic species of mycobacteria, catalyses the transfer of mycocerosic acids to the two hydroxyl groups at the common lipid core of phthiocerol, phthiodiolone, and phenolphthiocerol, forming dimycocerosate esters. The fatty acid precursors of mycocerosic acids are activated by EC 6.2.1.49, long-chain fatty acid adenylyltransferase FadD28, which loads them onto EC 2.3.1.111, mycocerosate synthase. That enzyme extends the precursors to form mycocerosic acids that remain attached until transferred by EC 2.3.1.282.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Onwueme, K.C., Ferreras, J.A., Buglino, J., Lima, C.D. and Quadri, L.E. Mycobacterial polyketide-associated proteins are acyltransferases: proof of principle with Mycobacterium tuberculosis PapA5. Proc. Natl. Acad. Sci. USA 101 (2004) 4608–4613. [PMID: 15070765]
2.  Buglino, J., Onwueme, K.C., Ferreras, J.A., Quadri, L.E. and Lima, C.D. Crystal structure of PapA5, a phthiocerol dimycocerosyl transferase from Mycobacterium tuberculosis. J. Biol. Chem. 279 (2004) 30634–30642. [PMID: 15123643]
3.  Chavadi, S.S., Onwueme, K.C., Edupuganti, U.R., Jerome, J., Chatterjee, D., Soll, C.E. and Quadri, L.E. The mycobacterial acyltransferase PapA5 is required for biosynthesis of cell wall-associated phenolic glycolipids. Microbiology 158 (2012) 1379–1387. [PMID: 22361940]
4.  Touchette, M.H., Bommineni, G.R., Delle Bovi, R.J., Gadbery, J.E., Nicora, C.D., Shukla, A.K., Kyle, J.E., Metz, T.O., Martin, D.W., Sampson, N.S., Miller, W.T., Tonge, P.J. and Seeliger, J.C. Diacyltransferase activity and chain length specificity of Mycobacterium tuberculosis PapA5 in the synthesis of alkyl β-diol lipids. Biochemistry 54 (2015) 5457–5468. [DOI] [PMID: 26271001]
[EC 2.3.1.282 created 2019]
 
 
EC 2.3.1.292     
Accepted name: (phenol)carboxyphthiodiolenone synthase
Reaction: (1) 3 malonyl-CoA + 2 (S)-methylmalonyl-CoA + icosanoyl-[(phenol)carboxyphthiodiolenone synthase] + 5 NADPH = C32-carboxyphthiodiolenone-[(phenol)carboxyphthiodiolenone synthase] + 5 CoA + 5 NADP+ + 5 CO2 + 2 H2O
(2) 3 malonyl-CoA + 2 (S)-methylmalonyl-CoA + docosanoyl-[(phenol)carboxyphthiodiolenone synthase] + 5 NADPH = C34-carboxyphthiodiolenone-[(phenol)carboxyphthiodiolenone synthase] + 5 CoA + 5 NADP+ + 5 CO2 + 2 H2O
(3) 3 malonyl-CoA + 2 (S)-methylmalonyl-CoA + 19-(4-hydroxyphenyl)-nonadecanoyl-[(phenol)carboxyphthiodiolenone synthase] + 5 NADPH = C37-(phenol)carboxyphthiodiolenone-[(phenol)carboxyphthiodiolenone synthase] + 5 CoA + 5 NADP+ + 5 CO2 + 2 H2O
(4) 3 malonyl-CoA + 2 (S)-methylmalonyl-CoA + 17-(4-hydroxyphenyl)heptadecanoyl-[(phenol)carboxyphthiodiolenone synthase] + 5 NADPH = C35-(phenol)carboxyphthiodiolenone-[(phenol)carboxyphthiodiolenone synthase] + 5 CoA + 5 NADP+ + 5 CO2 + 2 H2O
Glossary: C32-carboxyphthiodiolenone = (4E,9R,11R)-9,11-dihydroxy-2,4-dimethyl-3-oxotriacont-4-enoate
C34-carboxyphthiodiolenone = (4E,9R,11R)-9,11-dihydroxy-2,4-dimethyl-3-oxodotriacont-4-enoate
C35-phenolcarboxyphthiodiolenone = (4E)-9,11-dihydroxy-27-(4-hydroxyphenyl)-2,4-dimethyl-3-oxoheptacos-4-enoate
C37-phenolcarboxyphthiodiolenone = (4E,9R,11R)-9,11-dihydroxy-29-(4-hydroxyphenyl)-2,4-dimethyl-3-oxononacos-4-enoate
phthiocerols = linear carbohydrates containing one methoxyl group, one methyl group, and two secondary hydroxyl groups that serve as a backbone for certain lipids and glycolipids found in many species of Mycobacteriaceae
Other name(s): ppsABCDE (gene names)
Systematic name: (methyl)malonyl-CoA:long-chain acyl-[(phenol)carboxyphthiodiolenone synthase] (methyl)malonyltransferase {carboxyphthiodiolenone-[(phenol)carboxyphthiodiolenone synthase]-forming}
Comments: The enzyme, which is a complex of five polyketide synthase proteins, is involved in the synthesis of the lipid core common to phthiocerols and phenolphthiocerols. The first protein, PpsA, can accept either a C18 or C20 long-chain fatty acyl, or a (4-hydroxyphenyl)-C17 or C19 fatty acyl. The substrates must first be adenylated by EC 6.2.1.59, long-chain fatty acid adenylase/transferase FadD26, which also loads them onto PpsA. PpsA then extends them using a malonyl-CoA extender unit. The PpsB protein adds the next malonyl-CoA extender unit. The absence of a dehydratase and an enoyl reductase domains in the PpsA and PpsB modules results in the formation of the diol portion of the phthiocerol moiety. PpsC adds a third malonyl unit (releasing a water molecule due to its dehydratase domain), PpsD adds an (R)-methylmalonyl unit, releasing a water molecule, and PpsE adds a second (R)-methylmalonyl unit, without releasing a water molecule. The incorporation of the methylmalonyl units results in formation of two branched methyl groups in the elongated product. The enzyme does not contain a thioesterase domain [2], and release of the products requires the tesA-encoded type II thioesterase [1].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Rao, A. and Ranganathan, A. Interaction studies on proteins encoded by the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Mol. Genet. Genomics 272 (2004) 571–579. [PMID: 15668773]
2.  Trivedi, O.A., Arora, P., Vats, A., Ansari, M.Z., Tickoo, R., Sridharan, V., Mohanty, D. and Gokhale, R.S. Dissecting the mechanism and assembly of a complex virulence mycobacterial lipid. Mol. Cell 17 (2005) 631–643. [DOI] [PMID: 15749014]
[EC 2.3.1.292 created 2019]
 
 
EC 2.7.7.94      
Transferred entry: 4-hydroxyphenylalkanoate adenylyltransferase. Now EC 6.2.1.51, 4-hydroxyphenylalkanoate adenylyltransferase FadD29
[EC 2.7.7.94 created 2016, deleted 2017]
 
 
EC 2.7.7.95      
Transferred entry: mycocerosic acid adenylyltransferase. Now EC 6.2.1.49, long-chain fatty acid adenylyltransferase FadD28
[EC 2.7.7.95 created 2016, deleted 2017]
 
 
EC 2.7.7.98      
Transferred entry: 4-hydroxybenzoate adenylyltransferase. Now EC 6.2.1.50, 4-hydroxybenzoate adenylyltransferase FadD22
[EC 2.7.7.98 created 2017, deleted 2017]
 
 
EC 6.2.1.49     
Accepted name: long-chain fatty acid adenylyltransferase FadD28
Reaction: ATP + a long-chain fatty acid + holo-[mycocerosate synthase] = AMP + diphosphate + a long-chain acyl-[mycocerosate synthase] (overall reaction)
(1a) ATP + a long-chain fatty acid = diphosphate + a long-chain acyl-adenylate ester
(1b) a long-chain acyl-adenylate ester + holo-[mycocerosate synthase] = AMP + a long-chain acyl-[mycocerosate synthase]
Other name(s): fadD28 (gene name)
Systematic name: long-chain fatty acid:holo-[mycocerosate synthase] ligase (AMP-forming)
Comments: The enzyme, found in certain mycobacteria, activates long-chain fatty acids by adenylation and transfers them to EC 2.3.1.111, mycocerosate synthase. The enzyme participates in the biosynthesis of the virulent lipids dimycocerosates (DIM) and dimycocerosyl triglycosyl phenolphthiocerol (PGL).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Fitzmaurice, A.M. and Kolattukudy, P.E. Open reading frame 3, which is adjacent to the mycocerosic acid synthase gene, is expressed as an acyl coenzyme A synthase in Mycobacterium bovis BCG. J. Bacteriol. 179 (1997) 2608–2615. [DOI] [PMID: 9098059]
2.  Goyal, A., Yousuf, M., Rajakumara, E., Arora, P., Gokhale, R.S. and Sankaranarayanan, R. Crystallization and preliminary X-ray crystallographic studies of the N-terminal domain of FadD28, a fatty-acyl AMP ligase from Mycobacterium tuberculosis. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62 (2006) 350–352. [DOI] [PMID: 16582482]
3.  Arora, P., Goyal, A., Natarajan, V.T., Rajakumara, E., Verma, P., Gupta, R., Yousuf, M., Trivedi, O.A., Mohanty, D., Tyagi, A., Sankaranarayanan, R. and Gokhale, R.S. Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis. Nat. Chem. Biol. 5 (2009) 166–173. [DOI] [PMID: 19182784]
4.  Menendez-Bravo, S., Comba, S., Sabatini, M., Arabolaza, A. and Gramajo, H. Expanding the chemical diversity of natural esters by engineering a polyketide-derived pathway into Escherichia coli. Metab. Eng. 24 (2014) 97–106. [DOI] [PMID: 24831705]
5.  Vergnolle, O., Chavadi, S.S., Edupuganti, U.R., Mohandas, P., Chan, C., Zeng, J., Kopylov, M., Angelo, N.G., Warren, J.D., Soll, C.E. and Quadri, L.E. Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum. J. Bacteriol. 197 (2015) 1040–1050. [DOI] [PMID: 25561717]
[EC 6.2.1.49 created 2016 as EC 2.7.7.95, transferred 2017 to EC 6.2.1.49]
 
 
EC 6.2.1.50     
Accepted name: 4-hydroxybenzoate adenylyltransferase FadD22
Reaction: ATP + 4-hydroxybenzoate + holo-[4-hydroxyphenylalkanoate synthase] = AMP + diphosphate + 4-hydroxybenzoyl-[4-hydroxyphenylalkanoate synthase] (overall reaction)
(1a) ATP + 4-hydroxybenzoate = 4-hydroxybenzoyl-adenylate + diphosphate
(1b) 4-hydroxybenzoyl-adenylate + holo-[4-hydroxyphenylalkanoate synthase] = AMP + 4-hydroxybenzoyl-[4-hydroxyphenylalkanoate synthase]
Other name(s): fadD22 (gene name); 4-hydroxybenzoate adenylase
Systematic name: 4-hydroxybenzoate:holo-[4-hydroxyphenylalkanoate synthase] ligase (AMP-forming)
Comments: This mycobacterial enzyme participates in the biosynthesis of phenolphthiocerols. Following the substrate’s activation by adenylation, it is transferred to an acyl-carrier protein domain within the enzyme, from which it is transferred to EC 2.3.1.261, 4-hydroxyphenylalkanoate synthase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Simeone, R., Leger, M., Constant, P., Malaga, W., Marrakchi, H., Daffe, M., Guilhot, C. and Chalut, C. Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J. 277 (2010) 2715–2725. [DOI] [PMID: 20553505]
2.  Vergnolle, O., Chavadi, S.S., Edupuganti, U.R., Mohandas, P., Chan, C., Zeng, J., Kopylov, M., Angelo, N.G., Warren, J.D., Soll, C.E. and Quadri, L.E. Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum. J. Bacteriol. 197 (2015) 1040–1050. [DOI] [PMID: 25561717]
[EC 6.2.1.50 created 2017 as EC 2.7.7.98, transferred 2017 to EC 6.2.1.50]
 
 
EC 6.2.1.51     
Accepted name: 4-hydroxyphenylalkanoate adenylyltransferase FadD29
Reaction: (1) ATP + 17-(4-hydroxyphenyl)heptadecanoate + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + diphosphate + 17-(4-hydroxyphenyl)heptadecanoyl-[(phenol)carboxyphthiodiolenone synthase]
(1a) ATP + 17-(4-hydroxyphenyl)heptadecanoate = diphosphate + 17-(4-hydroxyphenyl)heptadecanoyl-adenylate
(1b) 17-(4-hydroxyphenyl)heptadecanoyl-adenylate + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + 17-(4-hydroxyphenyl)heptadecanoyl-[(phenol)carboxyphthiodiolenone synthase]
(2) ATP + 19-(4-hydroxyphenyl)nonadecanoate + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + diphosphate + 19-(4-hydroxyphenyl)nonadecanoyl-[(phenol)carboxyphthiodiolenone synthase]
(2a) ATP + 19-(4-hydroxyphenyl)nonadecanoate = diphosphate + 19-(4-hydroxyphenyl)nonadecanoyl-adenylate
(2b) 19-(4-hydroxyphenyl)nonadecanoyl-adenylate + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + 19-(4-hydroxyphenyl)nonadecanoyl-[(phenol)carboxyphthiodiolenone synthase]
Other name(s): fadD29 (gene name); 4-hydroxyphenylalkanoate adenylase
Systematic name: 4-hydroxyphenylalkanoate:holo-[(phenol)carboxyphthiodiolenone synthase] ligase
Comments: The mycobacterial enzyme participates in the biosynthesis of phenolphthiocerols. Following the substrate’s activation by adenylation, it is transferred to an acyl-carrier protein domain within the enzyme, from which it is transferred to the phenolphthiocerol/phthiocerol polyketide synthase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Simeone, R., Leger, M., Constant, P., Malaga, W., Marrakchi, H., Daffe, M., Guilhot, C. and Chalut, C. Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J. 277 (2010) 2715–2725. [DOI] [PMID: 20553505]
2.  Vergnolle, O., Chavadi, S.S., Edupuganti, U.R., Mohandas, P., Chan, C., Zeng, J., Kopylov, M., Angelo, N.G., Warren, J.D., Soll, C.E. and Quadri, L.E. Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum. J. Bacteriol. 197 (2015) 1040–1050. [DOI] [PMID: 25561717]
[EC 6.2.1.51 created 2016 as EC 2.7.7.94, transferred 2017 to EC 6.2.1.51]
 
 
EC 6.2.1.59     
Accepted name: long-chain fatty acid adenylase/transferase FadD26
Reaction: ATP + a long-chain fatty acid + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + diphosphate + a long-chain acyl-[(phenol)carboxyphthiodiolenone synthase] (overall reaction)
(1a) ATP + a long-chain fatty acid = diphosphate + a long-chain fatty-acyl adenylate ester
(1b) a long-chain fatty-acyl adenylate ester + holo-[(phenol)carboxyphthiodiolenone synthase] = AMP + a long-chain acyl-[(phenol)carboxyphthiodiolenone synthase]
Glossary: phthiocerols = linear carbohydrates containing one methoxyl group, one methyl group, and two secondary hydroxyl groups that serve as a backbone for certain lipids and glycolipids found in many species of Mycobacteriaceae
arachidate = icosanoate
behenate = docosanoate
lignocerate= tetracosanoate
Other name(s): FadD26
Systematic name: long-chain fatty acid:holo-[(phenol)carboxyphthiodiolenone synthase] ligase (AMP-forming)
Comments: The enzyme, present in pathogenic species of mycobacteria, participates in the pathway for biosynthesis of phthiocerols. It catalyses the adenylation of the long-chain fatty acids arachidate (C20) or behenate (C22) [1] and potentially the very-long-chain fatty acid lignocerate (C24) [2]. The activated fatty acids are then loaded to EC 2.3.1.292, (phenol)carboxyphthiodiolenone synthase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Azad, A.K., Sirakova, T.D., Fernandes, N.D. and Kolattukudy, P.E. Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J. Biol. Chem. 272 (1997) 16741–16745. [PMID: 9201977]
2.  Simeone, R., Leger, M., Constant, P., Malaga, W., Marrakchi, H., Daffe, M., Guilhot, C. and Chalut, C. Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J. 277 (2010) 2715–2725. [DOI] [PMID: 20553505]
3.  Vergnolle, O., Chavadi, S.S., Edupuganti, U.R., Mohandas, P., Chan, C., Zeng, J., Kopylov, M., Angelo, N.G., Warren, J.D., Soll, C.E. and Quadri, L.E. Biosynthesis of cell envelope-associated phenolic glycolipids in Mycobacterium marinum. J. Bacteriol. 197 (2015) 1040–1050. [DOI] [PMID: 25561717]
[EC 6.2.1.59 created 2019]
 
 


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