Differences and similarities in binding of pyruvate and l-lactate in the active site of M₄ and H₄ isoforms of human lactate dehydrogenase

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• 作者：Katarzyna &#x15a ; widerek ; Piotr Paneth
• 关键词：FEP ; BIE ; QM/MM ; Isoforms ; LDH
• 刊名：Archives of Biochemistry and Biophysics
• 出版年：2011
• 出版时间：1 January 2011
• 年：2011
• 卷：505
• 期：1
• 页码：33-41
• 全文大小：1254 K

文摘

We present QM/MM calculations that show differences in geometries of active sites of M₄ and H₄ isoforms of human LDH ligated with oxamate, pyruvate or l-lactate. As the consequence of these differences, binding isotope effects of the methyl hydrogen atoms of pyruvate and l-lactate may be used to experimentally distinguish these isoforms. Based on the FEP calculations we argue that l-lactate is a better candidate for the experimental studies. Our calculations of energies of interactions of ligands with the active site residues provide explanation for the observed experimentally sensitivity to inhibition of the M₄ isoenzyme isoform and pinpoint the differences to interactions of the ligand with the histidine residue. We conclude that pyruvate interacts much stronger in the active site of H₄ than M₄ isoform and that the latter interactions are weaker than with water molecules in the aqueous solution.