On Sept.15, 2009, Cancer Research published Zhi-Jie Liu group’s new progress on the structural studies of a key enzyme in the one-carbon metabolism titled‘Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues’ as cover story.

The folate-dependent one-carbon metabolic network supplies carbon for the synthesis of purines, thymidine, and amino acids.Several enzymes functioning in the network have been targeted successfully for the treatment of carcinomas.  hMTHFS (EC 6.3.3.2) catalyzes the initial irreversible conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, which regulates the flow of carbon through the one-carbon metabolic network. The activity of hMTHFS may affect the methylation of genome, completeness of DNA and RNA, the repair ability of DNA et.al. hMTHFS is also thought as a target in cancer therapy.

To date, relatively little is known about the structural basis for the mechanism of catalysis.Absence of the three-dimensional structure of hMTHFS has hampered the rational design and optimization of drug candidates. The study by Liu group shows 4 different complex forms of hMTHFS: native hMTHFS, binary complex of hMTHFS with ADP, hMTHFS bound with the N5-iminium phosphate reaction intermediate, and enzyme-product complex of hMTHFS. The N5-iminium phosphate captured for the first time in crystal structure unravels a unique strategy used by hMTHFS for recognition of the substrate and provides structural basis for the regulation of enzyme activity.hMTHFS structures and the mutagenesis data yield a coherent picture of the MTHFS active site, determinants of substrate specificity, and new insights into the mechanism of inhibition of hMTHFS.

Dr. Dong Wu, a postdoc research associate at Liu group, is the first author of this paper. Prof. Rongguang Zhang is also involved in this study. This work is supported by Ministry of Science and Technology of China,National Natural Science Foundation of China,Ministry of Health of China and Chinese Academy of Sciences.