P0A5P0 (CMAS2_MYCTU) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclopropane mycolic acid synthase 2
Short name=CMAS
EC=2.1.1.79

Alternative name(s):
Cyclopropane-fatty-acyl-phospholipid synthase
Short name=CFA synthase
Short name=Cyclopropane fatty acid synthase
Mycolic acid methyltransferase
Short name=MA-MT
S-adenosylmethionine-dependent methyltransferase
Short name=AdoMet-MT
Short name=SAM-MT

Gene names

Name:	cmaA2
Synonyms:	cma2, CMAS-2
Ordered Locus Names:	Rv0503c, MT0524
ORF Names:	MTCY20G9.30c

Organism

Mycobacterium tuberculosis [Reference proteome] [HAMAP]

Taxonomic identifier

1773 [NCBI]

Taxonomic lineage

cellular organisms › Bacteria › Actinobacteria › Actinobacteria › Actinobacteridae › Actinomycetales › Corynebacterineae › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis complex

Protein attributes

Sequence length	302 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the formation of trans cyclopropanated ketomycolate or methoxymycolate through the conversion of a double bond to a cyclopropane ring at the proximal position of an oxygenated mycolic acid via the transfer of a methylene group from S-adenosyl-L-methionine. In the absence of MmaA2, CmaA2 has a non-specific cis-cyclopropanating activity and is able to catalyze the conversion of a double bond to a cis cyclopropane ring at the distal position of an alpha mycolic acid. Cyclopropanated mycolic acids are key factors participating in cell envelope permeability, host immunomodulation and persistence. Ref.1 Ref.4
Catalytic activity	S-adenosyl-L-methionine + phospholipid olefinic fatty acid = S-adenosyl-L-homocysteine + phospholipid cyclopropane fatty acid.
Enzyme regulation	Inhibited by S-adenosyl-N-decyl-aminoethyl (SADAE) and thiacetazone (TAC). Ref.6 Ref.8
Pathway	Lipid metabolism; mycolic acid biosynthesis.
Subunit structure	Homodimer By similarity.
Subcellular location	Cytoplasm.
Disruption phenotype	Inactivation of cmaA2 causes accumulation of unsaturated derivatives of both the methoxy- and ketomycolates. The mycolic acids of the cmaA2 mutant lack trans-cyclopropane rings but are otherwise intact with respect to cyclopropane and methyl branch content. Deletion of cmaA2 has no effect on bacterial loads during mouse infection but causes hypervirulence due to an excessive immune activation which produces more-severe granulomatous pathology than wild-type, and increases both the macrophage activation and the macrophage inflammatory response. Ref.4 Ref.5 Ref.9
Miscellaneous	Was identified as a high-confidence drug target.
Sequence similarities	Belongs to the CFA/CMAS family.
Sequence caution	The sequence AAC43488.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence AAK44747.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Lipid biosynthesis Lipid metabolism
Cellular component	Cytoplasm
Ligand	S-adenosyl-L-methionine
Molecular function	Methyltransferase Transferase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	S-adenosylmethionine metabolic process Inferred from direct assay Ref.10. Source: MTBBASE modulation by symbiont of host innate immune response Inferred from mutant phenotype Ref.5. Source: MTBBASE mycolate cell wall layer assembly Inferred from direct assay Ref.1. Source: MTBBASE mycolic acid biosynthetic process Inferred from direct assay Ref.4Ref.9Ref.1PubMed 9694888. Source: MTBBASE response to hypoxia Inferred from expression pattern PubMed 15528667. Source: MTBBASE
Cellular_component	cytosol Inferred from direct assay PubMed 15525680. Source: MTBBASE plasma membrane Inferred from direct assay PubMed 14532352. Source: MTBBASE
Molecular_function	cyclopropane-fatty-acyl-phospholipid synthase activity Inferred from direct assay Ref.4PubMed 19477414Ref.1. Source: MTBBASE
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 302

302

Cyclopropane mycolic acid synthase 2

PRO_0000089569

Regions

Region

41 – 42

2

S-adenosyl-L-methionine binding

Region

76 – 84

9

S-adenosyl-L-methionine binding

Region

102 – 107

6

S-adenosyl-L-methionine binding

Region

131 – 132

2

S-adenosyl-L-methionine binding

Sites

Active site

284

1

By similarity

Secondary structure

1

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302

Helix Strand Turn

Details...

Helix

17 – 24

8

Helix

28 – 34

7

Helix

53 – 66

14

Beta strand

75 – 80

6

Helix

85 – 94

10

Beta strand

97 – 102

6

Helix

105 – 117

13

Beta strand

124 – 128

5

Helix

131 – 133

3

Beta strand

139 – 145

7

Helix

147 – 149

3

Helix

161 – 171

11

Beta strand

178 – 185

8

Helix

189 – 195

7

Helix

201 – 213

13

Helix

223 – 232

10

Beta strand

236 – 242

7

Helix

244 – 246

3

Helix

247 – 260

14

Helix

262 – 269

8

Helix

271 – 289

19

Beta strand

292 – 301

10

Sequences

	Sequence		Length	Mass (Da)
	P0A5P0 [UniParc]. Last modified March 15, 2005. Version 1. Checksum: 63AAA95627F95755	FASTA	302	34,660
	10 20 30 40 50 60 MTSQGDTTSG TQLKPPVEAV RSHYDKSNEF FKLWLDPSMT YSCAYFERPD MTLEEAQYAK 70 80 90 100 110 120 RKLALDKLNL EPGMTLLDIG CGWGSTMRHA VAEYDVNVIG LTLSENQYAH DKAMFDEVDS 130 140 150 160 170 180 PRRKEVRIQG WEEFDEPVDR IVSLGAFEHF ADGAGDAGFE RYDTFFKKFY NLTPDDGRML 190 200 210 220 230 240 LHTITIPDKE EAQELGLTSP MSLLRFIKFI LTEIFPGGRL PRISQVDYYS SNAGWKVERY 250 260 270 280 290 300 HRIGANYVPT LNAWADALQA HKDEAIALKG QETYDIYMHY LRGCSDLFRD KYTDVCQFTL VK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Identification and functional analysis of CMAS-2." George K.M., Yuan Y., Sherman D.R., Barry C.E. III J. Biol. Chem. 270:27292-27298(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION AS A CYCLOPROPANE SYNTHASE, NOMENCLATURE. Strain: ATCC 25618 / H37Rv.
[2]	"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence." Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K. , Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S., Barrell B.G. Nature 393:537-544(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: ATCC 25618 / H37Rv.
[3]	"Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains." Fleischmann R.D., Alland D., Eisen J.A., Carpenter L., White O., Peterson J.D., DeBoy R.T., Dodson R.J., Gwinn M.L., Haft D.H., Hickey E.K., Kolonay J.F., Nelson W.C., Umayam L.A., Ermolaeva M.D., Salzberg S.L., Delcher A., Utterback T.R. , Weidman J.F., Khouri H.M., Gill J., Mikula A., Bishai W., Jacobs W.R. Jr., Venter J.C., Fraser C.M. J. Bacteriol. 184:5479-5490(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: CDC 1551 / Oshkosh.
[4]	"The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-cyclopropane synthetase." Glickman M.S., Cahill S.M., Jacobs W.R. Jr. J. Biol. Chem. 276:2228-2233(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A TRANS-CYCLOPROPANE SYNTHASE, DISRUPTION PHENOTYPE. Strain: ATCC 35801 / TMC 107 / Erdman.
[5]	"Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence." Rao V., Gao F., Chen B., Jacobs W.R. Jr., Glickman M.S. J. Clin. Invest. 116:1660-1667(2006) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE. Strain: ATCC 25618 / H37Rv.
[6]	"Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria." Alahari A., Trivelli X., Guerardel Y., Dover L.G., Besra G.S., Sacchettini J.C., Reynolds R.C., Coxon G.D., Kremer L. PLoS ONE 2:E1343-E1343(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION. Strain: ATCC 25618 / H37Rv.
[7]	"targetTB: a target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis." Raman K., Yeturu K., Chandra N. BMC Syst. Biol. 2:109-109(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
[8]	"S-adenosyl-N-decyl-aminoethyl, a potent bisubstrate inhibitor of mycobacterium tuberculosis mycolic acid methyltransferases." Vaubourgeix J., Bardou F., Boissier F., Julien S., Constant P., Ploux O., Daffe M., Quemard A., Mourey L. J. Biol. Chem. 284:19321-19330(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION. Strain: ATCC 25618 / H37Rv.
[9]	"Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis cyclopropanation of oxygenated mycolates." Barkan D., Rao V., Sukenick G.D., Glickman M.S. J. Bacteriol. 192:3661-3668(2010) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE. Strain: ATCC 25618 / H37Rv.
[10]	"Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis." Huang C.-C., Smith C.V., Glickman M.S., Jacobs W.R. Jr., Sacchettini J.C. J. Biol. Chem. 277:11559-11569(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH S-ADENOSYL-L-METHIONINE AND SUBSTRATE ANALOG. Strain: ATCC 25618 / H37Rv.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U34637 Genomic DNA. Translation: AAC43488.1. Different initiation.
AE000516 Genomic DNA. Translation: AAK44747.1. Different initiation.
AL123456 Genomic DNA. Translation: CCP43240.1.

PIR

B70746.

RefSeq

NP_215017.1. NC_000962.3.
NP_334933.1. NC_002755.2.
YP_006513836.1. NC_018143.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KPI	X-ray	2.65	A	1-302	[»]
3HEM	X-ray	2.39	A	1-302	[»]

ProteinModelPortal

P0A5P0.

SMR

P0A5P0. Positions 12-302.

ModBase

Search...

Protein-protein interaction databases

STRING

83332.Rv0503c.

Proteomic databases

PRIDE

P0A5P0.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

EnsemblBacteria

AAK44747; AAK44747; MT0524.

GeneID

13318377.
887264.
923929.

KEGG

mtc:MT0524.
mtu:Rv0503c.

PATRIC

18122862. VBIMycTub22151_0565.

Organism-specific databases

TubercuList

Rv0503c.

Phylogenomic databases

eggNOG

COG2230.

HOGENOM

HOG000245191.

KO

K00574.

OMA

TLMAWHA.

ProtClustDB

CLSK790562.

Enzyme and pathway databases

BioCyc

MetaCyc:RV0503C-MONOMER.

UniPathway

UPA00915.

Family and domain databases

InterPro

IPR003333. Mycolic_cyclopropane_synthase.
[Graphical view]

Pfam

PF02353. CMAS. 1 hit.
[Graphical view]

PIRSF

PIRSF003085. CMAS. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

P0A5P0.

Entry information

Entry name

CMAS2_MYCTU

Accession

Primary (citable) accession number: P0A5P0
Secondary accession number(s): L0T3U0, Q11196

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	March 15, 2005
Last modified:	May 29, 2013
This is version 66 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Prokaryotic Protein Annotation Program