Structures of Plasmodium vivax serine hydroxymethyltransferase: implications for ligand‐binding specificity and functional control. (1st December 2014)

• Record Type: Journal Article
• Authors: Chitnumsub, Penchit; Jaruwat, Aritsara; Riangrungroj, Pinpunya; Ittarat, Wanwipa; Noytanom, Krittikar; Oonanant, Worrapoj; Vanichthanankul, Jarunee; Chuankhayan, Phimonphan; Maenpuen, Somchart; Chen, Chun‐Jung; Chaiyen, Pimchai; Yuthavong, Yongyuth; Leartsakulpanich, Ubolsree
• Is Part Of: Acta crystallographica. Volume 70:Part 12(2014:Dec.)
• Page Start: 3177
• Page End: 3186
• Publication Date: 2014-12-01
• Subjects: Biomolecules -- Structure -- Periodicals; Physical biochemistry -- Periodicals; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; 572
• DOI: 10.1107/S1399004714023128
• Languages: English
• ISSNs: 0907-4449

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>Plasmodium</italic> parasites, the causative agent of malaria, rely heavily on <italic>de novo</italic> folate biosynthesis, and the enzymes in this pathway have therefore been explored extensively for antimalarial development. Serine hydroxymethyltransferase (SHMT) from <italic>Plasmodium</italic> spp., an enzyme involved in folate recycling and dTMP synthesis, has been shown to catalyze the conversion of L‐ and D‐serine to glycine (Gly) in a THF‐dependent reaction, the mechanism of which is not yet fully understood. Here, the crystal structures of <italic>P. vivax</italic> SHMT (<italic>Pv</italic>SHMT) in a binary complex with L‐serine and in a ternary complex with D‐serine (D‐Ser) and (6<italic>R</italic>)‐5‐formyltetrahydrofolate (5FTHF) provide clues to the mechanism underlying the control of enzyme activity. 5FTHF in the ternary‐complex structure was found in the 6<italic>R</italic> form, thus differing from the previously reported structures of SHMT–Gly–(6<italic>S</italic>)‐5FTHF from other organisms. This suggested that the presence of D‐Ser in the active site can alter the folate‐binding specificity. Investigation of binding in the presence of D‐Ser and the (6<italic>R</italic>)‐ or (6<italic>S</italic>)‐5FTHF enantiomers indicated that both forms of 5FTHF can bind to the enzyme but that only (6<italic>S</italic>)‐5FTHF gives rise to a quinonoid intermediate. Likewise, a large surface area with a highly positively charged electrostatic potential surrounding the <italic>Pv</italic>SHMT folate pocket suggested a preference for a polyglutamated folate substrate similar to the mammalian SHMTs. Furthermore, as in <italic>P. falciparum</italic> SHMT, a redox switch created from a cysteine pair (Cys125–Cys364) was observed. Overall, these results assert the importance of features such as stereoselectivity and redox status for control of the activity and specificity of <italic>Pv</italic>SHMT.</p> </abstract>