Catalysis in Enzymatic Decarboxylations: Comparison of Selected Cofactor-Dependent and Cofactor-Independent Examples.

Abstract

This review is focused on three types of enzymes decarboxylating very different substrates: (1) Thiamin diphosphate (ThDP)-dependent enzymes reacting with 2-oxo acids; (2) Pyridoxal phosphate (PLP)-dependent enzymes reacting with α-amino acids; and (3) An enzyme with no known co-factors, orotidine 5'-monophosphate decarboxylase (OMPDC). While the first two classes have been much studied for many years, during the past decade studies of both classes have revealed novel mechanistic insight challenging accepted understanding. The enzyme OMPDC has posed a challenge to the enzymologist attempting to explain a 1017-fold rate acceleration in the absence of cofactors or even metal ions. A comparison of the available evidence on the three types of decarboxylases underlines some common features and more differences. The field of decarboxylases remains an interesting and challenging one for the mechanistic enzymologist notwithstanding the large amount of information already available.

Single‐Turnover Kinetics Reveal a Distinct Mode of Thiamine Diphosphate‐Dependent Catalysis in Vitamin K Biosynthesis

“…The proposed alignment of the scissile C 2α −COO − bond with the thiazolium ring in E‐Int 1 will allow the nascent anion in E‐Int* to distribute its charge to the thiazolium ring through conjugation. This transient conjugation should significantly reduce the nucleophilicity of the anion and greatly reduce the reverse reaction to counter the bouncing back of CO 2 , which was suggested to be a major obstacle to high reaction rates in enzymatic decarboxylation . After protonation of the transient anion, the nucleophilicity of the resulting E‐Int intermediate is further reduced to promote CO 2 separation, as demonstrated in model systems .…”

“…This coupling mechanism is able to protect the reactive enamine from side reactions by minimizing its exposure to the environment. In addition, it may be needed to counter the reversible decarboxylation and prevent CO 2 from “bouncing back” to the enamine intermediate . Currently, it is not clear whether a similar coupling mechanism operates in MenD catalysis.…”

Progress in the experimental observation of thiamin diphosphate-bound intermediates on enzymes and mechanistic information derived from these observations

“…This pK a in water for ThDP is 4.85 [48], while on the enzymes it ranges from 5.6 to 7.5 (Table 1, Refs. [27,52]). It was concluded from data in Table 1, that the pK a for the APH + coincides with the pH of optimum activity for each enzyme, indicating that all three forms IP, AP and APH + must be readily accessible during the catalytic cycle.…”

Theoretical study of the reaction mechanism of phenolic acid decarboxylase

“…Decarboxylases are increasingly used in organic synthesis, and mechanistic studies have attracted great interest . The information obtained here on the structures and energetics of the Bs PAD‐catalyzed reaction may help to further understand PAD‐type enzymes and to extend their biocatalytic applicability.…”