Abstract
Citric acid cycle comprises a various chemical reactions and it is required by all aerobic organisms to generate ATP. The present investigation focuses on the competitive inhibition of citrate synthase- the first step of the citric acid cycle. The known natural substrate of citrate synthase is acetyl Coenzyme A. Initially, the first substrate oxaloacetate binds to the citrate synthase which then induces the enzyme to change its conformation thus creating a binding site for the acetyl Coenzyme A. There are also several reports of citrate synthase enzyme inhibited by succinyl Coenzyme A which resembles acetyl Coenzyme A and acts as a competitive inhibitor. Hence, the present investigation deals with the molecular docking simulation studies of the two substrates viz. acetyl Coenzyme A and succinyl Coenzyme A at the active site of the citrate synthase to understand the insights into the competitive inhibition of these two substrates. Lastly, we have also performed the density functional theory (DFT) analysis of acetyl Coenzyme A and succinyl Coenzyme A to understand the atomic charge that might contribute in the competitive inhibition. The molecular docking scores and interaction energy revealed acetyl Coenzyme A showing competitive inhibition with succinyl Coenzyme A with favourable energy. Also the DFT studies revealed the plausible caused of the competitive inhibition at the atomic level.
Highlights
The citric acid or the Krebs cycle, [1] comprises a series of chemical reactions utilized by all aerobic organisms to generate its energy through the oxidation of acetate derived from carbohydrates, fats and proteins [2]
Molecular docking simulation was carried out using Molegro Virtual Docker (MVD)
The rerank score used in MVD is a weighted combination of the terms used by the MolDock score mixed with a few addition terms which includes the Steric terms which are Lennard-Jones approximations to the steric energy [16]
Summary
The citric acid or the Krebs cycle, [1] comprises a series of chemical reactions utilized by all aerobic organisms to generate its energy through the oxidation of acetate derived from carbohydrates, fats and proteins [2]. The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl Coenzyme A to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate) [5]. The enzyme citrate synthase catalyzes the condensation reaction of the two-carbon acetate residue from acetyl Coenzyme A and a molecule of four-carbon oxaloacetate to form the six-carbon citrate [5]. The enzyme citrate synthase is present in all living cells and stands as a pace-making enzyme in the first step of the Citric Acid Cycle [1]. Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, and it is commonly used as a quantitative enzyme marker for the presence of intact mitochondria
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