Molecular organization, catalytic mechanism and function of serine hydroxymethyltransferase - a potential target for cancer chemotherapy

Appaji Rao, N. ; Talwar, Rashmi ; Savithri, H. S. (2000) Molecular organization, catalytic mechanism and function of serine hydroxymethyltransferase - a potential target for cancer chemotherapy International Journal of Biochemistry & Cell Biology, 32 (4). pp. 405-416. ISSN 1357-2725

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Official URL: http://linkinghub.elsevier.com/retrieve/pii/S1357-...

Related URL: http://dx.doi.org/10.1016/S1357-2725(99)00126-0

Abstract

Serine hydroxymethyltransferase, a pyridoxal-5′-phosphate dependent enzyme, catalyzes the retro-aldol cleavage of serine to yield glycine and the hydroxymethyl group is transferred to 5,6,7,8-tetrahydrofolate to generate 5,10-methylene-H4-folate. The enzyme plays a pivotal role in channeling metabolites between amino acid and nucleotide metabolism. Dihydrofolate reductase and thymidylate synthase have been favorite targets for the development of anticancer drugs. However, development of resistance to drugs, due to a variety of reasons, has necessitated the identification of alternate targets for cancer chemotherapy and serine hydroxymethyltransferase is one such potential target. A detailed study of the kinetics of interaction of serine and folate analogs with this enzyme revealed several unique features that can be exploited for the design of new chemotherapeutic agents. The pathways for the reversible unfolding of the dimeric Escherichia coli and the tetrameric sheep liver enzyme, although different, revealed a requirement for the cofactor in the final step for generating an active enzyme. The gly A gene of Escherichia coli has been shown to code for this enzyme. Analysis of available gene sequences indicate that serine hydroxymethyltransferase is one of the most highly conserved proteins. The isolation of the cDNA clones for the enzyme and their overexpression in heterologous systems has enabled the probing of the molecular mechanisms of catalysis and the role of lysine, arginine and histidine in cofactor, substrate(s) binding and in maintaining the structure of the protein. Recently, the three-dimensional structure of the human liver serine hydroxymethyltransferase has been published. This, along with the information already available, provides a framework for the rational design of drugs targeted specifically towards this enzyme.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:SHMT; PLP; Inhibitors; Catalysis; Drug Design; X-ray Structure; Chemotherapeutic Target
ID Code:21201
Deposited On:20 Nov 2010 09:03
Last Modified:14 Jun 2011 08:28

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