The Enzyme Database

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EC 2.3.1.111     
Accepted name: mycocerosate synthase
Reaction: (1) a long-chain acyl-[mycocerosic acid synthase] + 3 methylmalonyl-CoA + 6 NADPH + 6 H+ = a trimethylated-mycocerosoyl-[mycocerosate synthase] + 3 CoA + 3 CO2 + 6 NADP+ + 3 H2O
(2) a long-chain acyl-[mycocerosic acid synthase] + 4 methylmalonyl-CoA + 8 NADPH + 8 H+ = a tetramethylated-mycocerosoyl-[mycocerosate synthase] + 4 CoA + 4 CO2 + 8 NADP+ + 4 H2O
Glossary: mycocerosic acid = a long-chain fatty acid with 3 or 4 methyl branches at positions 2,4,6 or 2,4,6,8, respectively. The carbon atoms bearing the methyl groups have the (R)-configuration.
Other name(s): mas (gene name); mycocerosic acid synthase; acyl-CoA:methylmalonyl-CoA C-acyltransferase (decarboxylating, oxoacyl- and enoyl-reducing); long-chain acyl-CoA:methylmalonyl-CoA C-acyltransferase (mycocerosate-forming)
Systematic name: long-chain acyl-[mycocerosic acid synthase]:methylmalonyl-CoA C-acyltransferase (mycocerosate-forming)
Comments: The enzyme, characterized from mycobacteria, is loaded with a long-chain acyl moiety by EC 6.2.1.49, long-chain fatty acid adenylyltransferase FadD28, and elongates it by incorporation of three or four methylmalonyl (but not malonyl) residues, to form tri- or tetramethyl-branched fatty-acids, respectively, such as 2,4,6,8-tetramethyloctacosanoate (C32-mycocerosate). Since the enzyme lacks a thioesterase domain, the product remains bound and requires additional enzyme(s) for removal. Even though the enzyme can accept C6 to C20 substrates in vitro, it prefers to act on C14-C20 substrates in vivo.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 95229-19-9
References:
1.  Rainwater, D.L. and Kollattukudy, P.E. Fatty acid biosynthesis in Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin. Purification and characterization of a novel fatty acid synthase, mycocerosic acid synthase, which elongates n-fatty acyl-CoA with methylmalonyl-CoA. J. Biol. Chem. 260 (1985) 616–623. [PMID: 3880746]
2.  Mathur, M. and Kolattukudy, P.E. Molecular cloning and sequencing of the gene for mycocerosic acid synthase, a novel fatty acid elongating multifunctional enzyme, from Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guerin. J. Biol. Chem. 267 (1992) 19388–19395. [PMID: 1527058]
3.  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]
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]
[EC 2.3.1.111 created 1989, modified 2016, modified 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 2.7.7.95      
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 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]
 
 


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