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–G...

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Bibliographic Details
Published in:Protein science 2003-09, Vol.12 (9), p.1954-1959
Main Authors: Vetting, Matthew W., Roderick, Steven L., Yu, Michael, Blanchard, John S.
Format: Article
Language:English
Subjects:
acetyl CoA
acetyltransferase
Acetyltransferases - chemistry
Amino Acid Motifs
Binding Sites
coenzyme A
Crystallography, X-Ray
Cysteine - chemistry
Databases as Topic
Disaccharides - chemistry
Glycopeptides
GNAT fold
Inositol
Models, Molecular
Multigene Family
Mycobacterium tuberculosis
Mycobacterium tuberculosis - enzymology
mycothiol
Mycothiol biosynthesis
mycothiol synthase
N-acetyltransferase
Plasmids - metabolism
Protein Conformation
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Pyrazoles - chemistry
Sulfhydryl Compounds - chemistry
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Summary: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 Å 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.
ISSN:0961-8368
1469-896X
DOI:10.1110/ps.03153703