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Overview

Mycobacterium tuberculosis NrdH is a small glutaredoxin-like protein involved in the electron transport chain that eventually leads to ribonucleotide reduction.

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Background

Mycobacterium tuberculosis Wikipediaresides in the lungs of a host and upon becoming active, results in symptoms such as chest pains, weakness, and intense coughing. Left untreated and unmanaged, TB can lead to death (1.5 million in 2013). The disease has a high co-morbidity with HIV/AIDS due to its immunocompromising tendencies. Tuberculosis is one of the most heavily studied diseases today. With over 9 million infections worldwide per year, the necessity for antimicrobial agents to combat emerging multi-drug resistant strands is imperative.

MtNrdH has been identified as an electron carrier protein in ribonuleotide reduction. Ribonucleotide reduction uses an enzyme called ribonucleotide reductase (RNR) to make deoxyribonucleotides, which act as precursors to DNA synthesis. Three classes of RNRs have been identified; each class differs in cofactor requirement, structure, and oxygen dependence, but the general catalytic mechanism is conserved in all three classes. Mycobacterium tuberculosis uses class I ribonucleotide reductase.

Class I RNR is further subdivided into class Ia and Ib. Both Ia and Ib reduce ribonucleotide 5’ diphosphate to deoxyribonucleotide 5’ diphosphate (NDP to dNDP). After ribonucleotide reductase performs the first round of reduction, RNR must be reduced again to reset the cycle. In class Ib, RNR is reduced by either glutadoxin or thiordoxin, which are first reduced by glutadoxin reductase and thiordoxin reductase, respectively. In class Ib, RNR is reduced by NrdE, which is first reduced by NrdH. An important distinction between Ia and Ib is that Ia is present in eukaryotes, eubacteria, bacteriophages, and virus, but Ib is only present in eubacteria.

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Ribonucleotide Reduction Class Ib general mechanism. The role of NrdH is highlighted.

Structure

The structure of M. tuberculosis as determined by x-ray crystallography has 79 residues in a single polypeptide chain. . The active site (shown in green) is dominated by a disulphide bond between Cys-11 and Cys-14, which serves as the site of reduction by Theirodoxin reductase.

The active site of the protein is stabilized through a network of hydrogen bonds involving the two highly conserved residues, CVQC and WSGFRP. The crystal structure shows that interactions with one water molecule is necessary for the proper coordination between the conserved motifs to occur. These hydrogen bonds orient the important residues in the most optimal position to promote oxidation and reduction.

Function

Disease

Relevance

Similar structures of NrdH have been isolated in other primitive species including E. coli, S. pyogenes, S. typhimurium, D. deserti, S. flexneri 2457T, and S. dysenteriae. In higher order multi-cellular organisms, however the NrdH protein is replaced by more complex glutaredoxins or theirodoxins. This observation leads some to speculate that NrdH is one of the very first ancestors in the ribonucleotide reduction pathway. If this is true, NrdH can be seen as a critical protein that allowed for the development of DNA-based life since deoxyribonucleotides could not have existed without the ribonucleotide reduction pathway. A better understanding of the evolutionary timeline of NrdH and similar proteins could shed greater light onto the RNA Wold Hypothesis, specifically describing the time frame of emergence of DNA based life.

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.Jmol reference ^[2] article describing Jmol ^[3]