Sandbox Reserved 1059

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This Sandbox is Reserved from 02/09/2015, through 05/31/2016 for use in the course "CH462: Biochemistry 2" taught by Geoffrey C. Hoops at the Butler University. This reservation includes Sandbox Reserved 1051 through Sandbox Reserved 1080.

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Contents 1 NrdH of Mycobacterium tuberculosis 2 Function 3 Structure 3.1 Conserved Motifs 4 Chemical Processes 5 Disease 6 Relevance 7 References

NrdH of Mycobacterium tuberculosis

NrdH is a redox protein part of a family of redox proteins. The other proteins that maintain the redox balance of this protein are three Thioredoxin and three glutaredoxin-like proteins. Prokaryotes typically maintain redox homeostasis through low-molecular weight thiols (glutathione) and through proteins invovled in disulfide exchange (thioredoxins).

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Function

The main function is to act as a reducing partner of class 1B ribonucleotide reductase and for ribonucleotide reduction (RR), it is thought to supply electrons for this biochemical reaction. RR is one of the most fundamental biochemical processes that is required for DNA based life form to exist. Ribonucleotide reductases (RNRs) produce deoxyribonucleotides. These are precursors for DNA synthesis. ^[1].

Structure

The tertiary structure of NrdH has a thioredoxin fold with 79 residues with a glutaredoxin-like sequence. However, unlike glutaredoxins, NrdH of Mycobacterium tuberculosis can accept electrons from thioredoxin reductase. The binding site of NrdH is specific for aromatic amino acids ^[1].

Conserved Motifs

Members of the NrdH family are typically characterized by CVQC and WSGFRP

Within the , the amide oxygen of glutamine residue is firmly hydrogen bonded with the peptidyl nitrogen of Phe-44. The amide nitrogen of glutamine is then available for further hydrogen bonding. The carbonyl oxygen of Val-12 hydrogen bonds with peptidyl nitrogen of Ala-16. ^[1] . The residues between the two cysteines are known to affect redox potentials and pKa values. Also, by changing the target proteins, in turn, they regulate the function. The N-terminal cysteine acts as a nucleophile, whereas the C-terminal cysteine acts as a resolving cysteine ^[1].

The is stabilized by glutamine of the CVQC motif and phenylalanine is exposed to the solvent. Phe-64 and Val-12 with Ala-16 and Ala-20 create a distinct hydrophobic patch that is exposed to the solvent. This patch is of functional significance that could potentially interact with the C-terminus of RNR. This hydrogen bonding network lends to the stability of the redox active site ^[1].

Chemical Processes

NrdH is able to accept electrons from M. tuberculosis thioredoxin reductase and is able to reduce the disulfide bonds that are present in insulin ^[1].

Disease

Relevance

Genes that encode for NrdE and NrdF are essential for growth and RR might be an attractive biochemical pathway for antimycobacterial drug discovery. Organisms that depend solely on class 1B RNR could potentially be the essential genes and potential drug targets for treating tuberculosis ^[1].

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References

1. ↑ ^{1.0 1.1 1.2 1.3 1.4 1.5 1.6} ...<ref>Phulera, S. and Mande, S. (2013). The crystal structure of ''Mycobacterium tuberculosis'' NrdH at 0.87 Angstrom suggests a possible mode of its activity. ''Biochemistry'' 53: 4056-4065. DOI 10.1021/bi400191z</li></ol></ref>