Crystal structure of mycothiol synthase (Rv0819) from Mycobacterium tuberculosis shows structural homology to the GNAT family of N-acetyltransferases.
Mycothiol is the predominant low-molecular weight thiol produced by actinomycetes, including Mycobacterium tuberculosis. The last reaction in the biosynthetic pathway for mycothiol is catalyzed by mycothiol synthase (MshD), which acetylates the cysteinyl amine of cysteine-glucosamine-inositol (Cys-GlcN-Ins). The crystal structure of MshD was determined in the presence of coenzyme A and acetyl-CoA. MshD consists of two tandem-repeated domains, each exhibiting the Gcn5-related N-acetyltransferase (GNAT) fold. These two domains superimpose with a root-mean-square deviation of 1.7 A over 88 residues, and each was found to bind one molecule of coenzyme, although the binding sites are quite different. The C-terminal domain has a similar active site to many GNAT members in which the acetyl group of the coenzyme is presented to an open active site slot. However, acetyl-CoA bound to the N-terminal domain is buried, and is apparently not positioned to promote acetyl transfer. A modeled substrate complex indicates that Cys-GlcN-Ins would only fill a portion of a negatively charged channel located between the two domains. This is the first structure determined for an enzyme involved in the biosynthesis of mycothiol.
Vetting
Matthew W
MW
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Roderick
Steven L
SL
Yu
Michael
M
Blanchard
John S
JS
D000123:Acetyltransferases / Q000737:chemistry*; D020816:Amino Acid Motifs; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D019992:Databases as Topic; D004187:Disaccharides / Q000737:chemistry; D006020:Glycopeptides; D007294:Inositol; D008958:Models, Molecular; D005810:Multigene Family; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010957:Plasmids / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry
D004187:Disaccharides; D006020:Glycopeptides; D011720:Pyrazoles; D013438:Sulfhydryl Compounds; C089265:mycothiol; D007294:Inositol; D000123:Acetyltransferases; C470312:acetyl-CoA 1-D-myo-inosityl 2-L-cysteinylamido-2-deoxy-alpha-D-glucopyranoside acetyltransferase; D003545:Cysteine