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Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition.
FEBS J. 2014 Jun; 281(11):2570-83.FJ

Abstract

Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a hydroxymethyl group from l-serine to tetrahydrofolate to yield glycine and 5,10-methylenetetrahydrofolate. Our previous investigations have shown that SHMTs from Plasmodium spp. (P. falciparum, Pf; P. vivax, Pv) are different from the enzyme from rabbit liver in that Plasmodium SHMT can use d-serine as a substrate. In this report, the biochemical and biophysical properties of the Plasmodium and the human cytosolic form (hcSHMT) enzymes including ligand binding and kinetics were investigated. The data indicate that, similar to Plasmodium enzymes, hcSHMT can use d-serine as a substrate. However, hcSHMT displays many properties that are different from those of the Plasmodium enzymes. The molar absorption coefficient of hcSHMT-bound pyridoxal-5'-phosphate (PLP) is much greater than PvSHMT-bound or PfSHMT-bound PLP. The binding interactions of hcSHMT and Plasmodium SHMT with d-serine are different, as only the Plasmodium enzyme undergoes formation of a quinonoid-like species upon binding to d-serine. Furthermore, it has been noted that hcSHMT displays strong substrate inhibition by tetrahydrofolate (THF) (at THF > 40 μm), compared with SHMTs from Plasmodium and other species. The pH-activity profile of hcSHMT shows higher activities at lower pH values corresponding to a pKa value of 7.8 ± 0.1. Thiosemicarbazide reacts with hcSHMT following a one-step model [k1 of 12 ± 0.6 m(-1) ·s(-1) and k-1 of (1.0 ± 0.6) × 10(-3) s(-1) ], while the same reaction with PfSHMT involves at least three steps. All data indicated that the ligand binding environment of SHMT from human and Plasmodium are different, indicating that it should be possible to develop species-selective inhibitors in future studies.

DATABASE

serine hydroxymethyltransferase, EC 2.1.2.1; 5,10-methylenetetrahydrofolate dehydrogenase, EC 1.5.1.5.

Authors+Show Affiliations

Department of Biochemistry and Center of Excellence in Protein Structure and Function, Mahidol University, Bangkok, Thailand.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24698160

Citation

Pinthong, Chatchadaporn, et al. "Distinct Biochemical Properties of Human Serine Hydroxymethyltransferase Compared With the Plasmodium Enzyme: Implications for Selective Inhibition." The FEBS Journal, vol. 281, no. 11, 2014, pp. 2570-83.
Pinthong C, Maenpuen S, Amornwatcharapong W, et al. Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition. FEBS J. 2014;281(11):2570-83.
Pinthong, C., Maenpuen, S., Amornwatcharapong, W., Yuthavong, Y., Leartsakulpanich, U., & Chaiyen, P. (2014). Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition. The FEBS Journal, 281(11), 2570-83. https://doi.org/10.1111/febs.12803
Pinthong C, et al. Distinct Biochemical Properties of Human Serine Hydroxymethyltransferase Compared With the Plasmodium Enzyme: Implications for Selective Inhibition. FEBS J. 2014;281(11):2570-83. PubMed PMID: 24698160.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition. AU - Pinthong,Chatchadaporn, AU - Maenpuen,Somchart, AU - Amornwatcharapong,Watcharee, AU - Yuthavong,Yongyuth, AU - Leartsakulpanich,Ubolsree, AU - Chaiyen,Pimchai, Y1 - 2014/04/28/ PY - 2013/12/17/received PY - 2014/03/25/revised PY - 2014/03/31/accepted PY - 2014/4/5/entrez PY - 2014/4/5/pubmed PY - 2014/7/30/medline KW - PLP-dependent enzyme KW - dTMP cycle KW - folate metabolism KW - pyridoxal-5′-phosphate KW - serine hydroxymethyltransferase SP - 2570 EP - 83 JF - The FEBS journal JO - FEBS J. VL - 281 IS - 11 N2 - UNLABELLED: Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a hydroxymethyl group from l-serine to tetrahydrofolate to yield glycine and 5,10-methylenetetrahydrofolate. Our previous investigations have shown that SHMTs from Plasmodium spp. (P. falciparum, Pf; P. vivax, Pv) are different from the enzyme from rabbit liver in that Plasmodium SHMT can use d-serine as a substrate. In this report, the biochemical and biophysical properties of the Plasmodium and the human cytosolic form (hcSHMT) enzymes including ligand binding and kinetics were investigated. The data indicate that, similar to Plasmodium enzymes, hcSHMT can use d-serine as a substrate. However, hcSHMT displays many properties that are different from those of the Plasmodium enzymes. The molar absorption coefficient of hcSHMT-bound pyridoxal-5'-phosphate (PLP) is much greater than PvSHMT-bound or PfSHMT-bound PLP. The binding interactions of hcSHMT and Plasmodium SHMT with d-serine are different, as only the Plasmodium enzyme undergoes formation of a quinonoid-like species upon binding to d-serine. Furthermore, it has been noted that hcSHMT displays strong substrate inhibition by tetrahydrofolate (THF) (at THF > 40 μm), compared with SHMTs from Plasmodium and other species. The pH-activity profile of hcSHMT shows higher activities at lower pH values corresponding to a pKa value of 7.8 ± 0.1. Thiosemicarbazide reacts with hcSHMT following a one-step model [k1 of 12 ± 0.6 m(-1) ·s(-1) and k-1 of (1.0 ± 0.6) × 10(-3) s(-1) ], while the same reaction with PfSHMT involves at least three steps. All data indicated that the ligand binding environment of SHMT from human and Plasmodium are different, indicating that it should be possible to develop species-selective inhibitors in future studies. DATABASE: serine hydroxymethyltransferase, EC 2.1.2.1; 5,10-methylenetetrahydrofolate dehydrogenase, EC 1.5.1.5. SN - 1742-4658 UR - https://www.unboundmedicine.com/medline/citation/24698160/Distinct_biochemical_properties_of_human_serine_hydroxymethyltransferase_compared_with_the_Plasmodium_enzyme:_implications_for_selective_inhibition_ L2 - https://doi.org/10.1111/febs.12803 DB - PRIME DP - Unbound Medicine ER -