Structural and energy basis of the ligand 2-hydroxymuconate (2HM) under the enzymatic complex of 4-oxalocrotonate Tautomerase

Chaton, Kham Lek (2023) Structural and energy basis of the ligand 2-hydroxymuconate (2HM) under the enzymatic complex of 4-oxalocrotonate Tautomerase. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Kham Lek Chaton (18MS134)) Thesis_18MS134.pdf - Submitted Version Restricted to Repository staff only Download (2MB)

Abstract

4-Oxalocrotonate tautomerase (4-OT) catalyses the tautomerism reaction of 2oxo-4-hexenedioate (2o4hex). Where in H from carbon 3 in 2o4hex is shifted to carbon 5. Thus, giving a stable product conformation that is 2-oxo-3-hexadienedioate (2o3hex). The reaction is catalysed through an intermediate that is deprotonated 2-Hydroxymuconate (2HM). However some studies have found that protonated 2HM is catalysed faster than 2o4hex as the starting substrate. In fact it is still unclear which substrate is turned over faster into the product by the enzyme (4-OT). While trying to propose a detailed reaction mechanism taking 2HM as the starting substrate. Our study has found that the existence of 2HM is rather peculiar with respect to its structure. 2HM is 180° rotated in its active site and awkwardly bent in some cases. And surprisingly, Free energy perturbation calculation shows the stability of the rotated 180° 2HM is more by ΔΔG of 2.60 kJ/mol relative to normal 2HM. Quantum mechanical calculation also verifies the stability of the rotated 2HM. And the bend structure also shows a transition state. Therefore, it may serve as a new form of substrate that can be catalysed by the enzyme 4-Oxalocrotonate tautomerase (4-OT).

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