The role of remote flavin adenine dinucleotide pieces in the oxidative decarboxylation catalyzed by salicylate hydroxylase

Pereira, Mozart S.; Araújo, Simara Semíramis de; Nagem, R.A.P.; Richard, John P.; Brandão, Tiago A. S.

doi:10.1016/j.bioorg.2021.105561

Cited by 4 publications

(3 citation statements)

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“…Cofactors for enzymatic reactions consist of compact reactive functional groups that are attached to large accessory handles that do not participate in the reaction chemistry but provide binding energy that may be used either for stabilization of the ground-state Michaelis complex or to provide for specificity in transition state binding. This specificity was thoroughly documented by Jencks and coworkers, beginning in 1976, for the thioester coenzyme-A handle in catalysis by succinyl-CoA:3-oxoacid CoA transferase. − There have been few studies to extend these seminal experimental results to other cofactors …”

Section: Introductionmentioning

confidence: 99%

“…18−21 There have been few studies to extend these seminal experimental results to other cofactors. 22 The nicotinamide adenine dinucleotide (NAD) cofactor participates in enzyme-catalyzed oxidation−reduction reactions that are central to cell metabolism. The cofactor consists of the reactive nicotinamide fragment that undergoes oxidation−reduction chemistry and an adenosine 5′-diphosphate-ribose (ADP-ribose) handle (Scheme 1) that interacts with the protein at the Michaelis complex.…”

Section: ■ Introductionmentioning

confidence: 99%

“… 18 − 21 There have been few studies to extend these seminal experimental results to other cofactors. 22 …”

Section: Introductionmentioning

confidence: 99%

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Utilization of Cofactor Binding Energy for Enzyme Catalysis: Formate Dehydrogenase-Catalyzed Reactions of the Whole NAD Cofactor and Cofactor Pieces

2023

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The pressure to optimize enzymatic rate accelerations has driven the evolution of the induced-fit mechanism for enzyme catalysts where the binding interactions of nonreacting phosphodianion or adenosyl substrate pieces drive enzyme conformational changes to form protein substrate cages that are activated for catalysis. We report the results of experiments to test the hypothesis that utilization of the binding energy of the adenosine 5′-diphosphate ribose (ADP-ribose) fragment of the NAD cofactor to drive a protein conformational change activates Candida boidinii formate dehydrogenase (CbFDH) for catalysis of hydride transfer from formate to NAD+. The ADP-ribose fragment provides a >14 kcal/mol stabilization of the transition state for CbFDH-catalyzed hydride transfer from formate to NAD+. This is larger than the ca. 6 kcal/mol stabilization of the ground-state Michaelis complex between CbFDH and NAD+ (K NAD = 0.032 mM). The ADP, AMP, and ribose 5′-phosphate fragments of NAD+ activate CbFDH for catalysis of hydride transfer from formate to nicotinamide riboside (NR). At a 1.0 M standard state, these activators stabilize the hydride transfer transition states by ≈5.5 (ADP), 5.5 (AMP), and 4.4 (ribose 5′-phosphate) kcal/mol. We propose that activation by these cofactor fragments is partly or entirely due to the ion-pair interaction between the guanidino side chain cation of R174 and the activator phosphate anion. This substitutes for the interaction between the α-adenosyl pyrophosphate anion of the whole NAD+ cofactor that holds CbFDH in the catalytically active closed conformation.

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