Mycothiol: synthesis, biosynthesis and biological functions of the major low molecular weight thiol in actinomycetes

Jothivasan, Vishnu Karthik; Hamilton, Chris J.

doi:10.1039/b616489g

Cited by 135 publications

(121 citation statements)

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“…If the modified nicotinamide ring proposed to be generated by this pathway retains its properties then it is conceivable that the metabolite synthesized by these systems might function as a soluble antioxidant comparable to the peptide antioxidants, such as glutathione, mycothiol and bacillithiol. 11,87,88 However, given the extensive modification, it is also possible that it is a secondary metabolite that has biochemical properties entirely distinct from NAD or NADP and has an unrelated role.…”

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Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Souza

Aravind

2012

Mol. BioSyst.

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Nicotinamide adenine dinucleotide (NAD) is a ubiquitous cofactor participating in numerous redox reactions. It is also a substrate for regulatory modifications of proteins and nucleic acids via the addition of ADP-ribose moieties or removal of acyl groups by transfer to ADP-ribose. In this study, we use in-depth sequence, structure and genomic context analysis to uncover new enzymes and substrate-binding proteins in NAD-utilizing metabolic and macromolecular modification systems. We predict that Escherichia coli YbiA and related families of domains from diverse bacteria, eukaryotes, large DNA viruses and single strand RNA viruses are previously unrecognized components of NAD-utilizing pathways that probably operate on ADP-ribose derivatives. Using contextual analysis we show that some of these proteins potentially act in RNA repair, where NAD is used to remove 2 0 -3 0 cyclic phosphodiester linkages. Likewise, we predict that another family of YbiA-related enzymes is likely to comprise a novel NAD-dependent ADP-ribosylation system for proteins, in conjunction with a previously unrecognized ADP-ribosyltransferase. A similar ADP-ribosyltransferase is also coupled with MACRO or ADP-ribosylglycohydrolase domain proteins in other related systems, suggesting that all these novel systems are likely to comprise pairs of ADP-ribosylation and ribosylglycohydrolase enzymes analogous to the DraG-DraT system, and a novel group of bacterial polymorphic toxins. We present evidence that some of these coupled ADP-ribosyltransferases/ribosylglycohydrolases are likely to regulate certain restriction modification enzymes in bacteria. The ADP-ribosyltransferases found in these, the bacterial polymorphic toxin and host-directed toxin systems of bacteria such as Waddlia also throw light on the evolution of this fold and the origin of eukaryotic polyADP-ribosyltransferases and NEURL4-like ARTs, which might be involved in centrosomal assembly. We also infer a novel biosynthetic pathway that might be involved in the synthesis of a nicotinate-derived compound in conjunction with an asparagine synthetase and AMPylating peptide ligase. We use the data derived from this analysis to understand the origin and early evolutionary trajectories of key NAD-utilizing enzymes and present targets for future biochemical investigations.

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Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Souza

Aravind

2012

Mol. BioSyst.

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“…Instead, these organisms use the small molecule mycothiol (MSH) 2 as their primary reducing agent and in xenobiotic metabolism for the detoxification of drugs and other toxins (1)(2)(3)(4). MSH is likely to be critical for the survival of mycobacteria inside activated macrophages, where the mycobacteria are subjected to oxidative bursts.…”

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The Activity and Cofactor Preferences of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Change Depending on Environmental Conditions

Huang

Kocabas

Hernick

2011

Journal of Biological Chemistry

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2 as their primary reducing agent and in xenobiotic metabolism for the detoxification of drugs and other toxins (1-4). MSH is likely to be critical for the survival of mycobacteria inside activated macrophages, where the mycobacteria are subjected to oxidative bursts. Consequently, the enzymes involved in MSH biosynthesis and detoxification (Fig. 1A), including the metalloenzymes N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-␣-D-glucopyranoside deacetylase (MshB) and MSH-conjugate amidase, are targets for the development of antibiotics for the treatment of diseases such as tuberculosis (5-10).The enzyme MshB catalyzes the hydrolysis of (GlcN-Ins) and acetate, the fourth overall step in MSH biosynthesis (rate-limiting step) (11). MshB is an attractive drug target because it is a metalloenzyme; there are past successes in targeting metalloenzymes, including inhibitors of carbonic anhydrase, matrix metalloproteases, and angiotensinconverting enzyme (12-15). Inhibitors of metalloenzymes typically contain a group that binds to the catalytic metal ion. Consequently, a comprehensive understanding of metalloenzyme cofactor preferences is necessary for the development of potent and specific metalloenzyme inhibitors.MshB was previously identified as a Zn 2ϩ -dependent enzyme based on the observations that the enzyme copurifies with Zn 2ϩ (Fig. 1B) and that the enzyme activity is reversibly inhibited by treatment with 1,10-phenanthroline (16 -18). On the basis of the structure of the enzyme active site, MshB is thought to catalyze the hydrolysis of GlcNAc-Ins via one of two potential chemical mechanisms using general acid-base catalysis (GABC) (19). One possible mechanism uses a single bifunctional GABC to facilitate the hydrolysis of GlcNAc-Ins, whereas the other uses a GABC pair to carry out this reaction. However, Fe 2ϩ was not examined as a potential cofactor in these experiments. Furthermore, MshB was purified using zinc immobilized metal ion affinity chromatography (IMAC) under aerobic conditions, which is biased toward zinc incorporation into metalloenzymes (16). Purified MshB contains nickel (0.82 eq) when purified using nickel IMAC (aerobic conditions) (16). There have been several examples over the last decade of Fe 2ϩ -enzymes being misidentified as exclusive Zn 2ϩ -enzymes, including peptide deformylase, S-ribosylhomocysteinase (LuxS), UDP-3-O-(R-3-hydroxymyristoyl)-Nacetylglucosamine deacetylase (LpxC), and possibly histone deacetylase-8 (HDAC8) (20 -27). In all these enzymes, the Fe 2ϩ cofactor is either exclusively preferred or is preferred over Zn 2ϩ under certain environmental conditions. The

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“…In contrast to eukaryotes and other bacteria, these organisms do not have glutathione. Instead, they use the small molecule mycothiol (MSH) 2 as their primary reducing agent and in xenobiotic metabolism for the detoxification of drugs and other toxins (1)(2)(3)(4). MSH is probably critical for survival of mycobacteria inside the oxidative environment of activated macrophages where they reside.…”

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confidence: 99%

Examination of Mechanism of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Reveals Unexpected Role for Dynamic Tyrosine

Huang

Hernick

2012

Journal of Biological Chemistry

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Background: MshB is a metal-dependent deacetylase involved in mycothiol biosynthesis. Results:The reaction proceeds via a general acid-base pair mechanism and uses a dynamic Tyr that modulates substrate binding, chemistry, and product release. Conclusion:The catalytic mechanism differs from a prototypical metalloprotease mechanism. Significance: Key side chains identified in these studies can be targeted for inhibitor development.

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Mycothiol: synthesis, biosynthesis and biological functions of the major low molecular weight thiol in actinomycetes

Cited by 135 publications

References 146 publications

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

The Activity and Cofactor Preferences of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Change Depending on Environmental Conditions

Examination of Mechanism of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Reveals Unexpected Role for Dynamic Tyrosine

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