Thiamin diphosphate in biological chemistry: analogues of thiamin diphosphate in studies of enzymes and riboswitches

Abstract

The role of thiamin diphosphate (ThDP) as a cofactor for enzymes has been known for many decades. This minireview covers the progress made in understanding the catalytic mechanism of ThDP‐dependent enzymes through the use of ThDP analogues. Many such analogues have been synthesized and have provided information on the functional groups necessary for the binding and catalytic activity of the cofactor. Through these studies, the important role of hydrophobic interactions in stabilizing reaction intermediates in the catalytic cycle has been recognized. Stable analogues of intermediates in the ThDP‐catalysed reaction mechanism have also been synthesized and crystallographic studies using these analogues have allowed enzyme structures to be solved that represent snapshots of the reaction in progress. As well as providing mechanistic information about ThDP‐dependent enzymes, many analogues are potent inhibitors of these enzymes. The potential of these compounds as therapeutic targets and as important herbicidal agents is discussed. More recently, the way that ThDP regulates the genes for its own biosynthesis through the action of riboswitches has been discovered. This opens a new branch of thiamin research with the potential to provide new therapeutic targets in the fight against infection.

Ion pair liquid chromatography method for the determination of thiamine (vitamin B1) homeostasis

“…There is about 30 mg of thiamine in an average adult individual, of which approximately 80% is the form of thiamine pyrophosphate (TPP) (Finglas, 1993). TPP plays a vital role in cellular energy homeostasis as a coenzyme for three enzyme complexes in both major carbohydrate pathways: the pyruvate dehydrogenase complex, responsible for the oxidative decarboxylation of pyruvate and formation of acetyl CoA which provides the link between glycolysis and the trichloroacetic acid (TCA) cycle; the α-ketoglutarate dehydrogenase complex, a key enzyme in the TCA cycle that is structurally related to the pyruvate dehydrogenase complex; and transketolase of the pentose phosphate pathway (Agyei-Owusu and Leeper, 2009). Although thiamine deficiency is rare in Western societies, it can still be found in alcoholics owing to a combination of poor diet (Tallaksen et al, 1992) and inhibition of intestinal thiamine absorption by alcohol associated with a significant reduction in expression of thiamine transporters at both protein and mRNA levels (Subramanya et al, 2010).…”

Prostatic Acid Phosphatase Is Required for the Antinociceptive Effects of Thiamine and Benfotiamine

“…Thiamine exists as the free molecule as well as in the form of several phosphate esters: thiamine monophosphate (TMP), thiamine diphosphate (TDP, also called thiamine pyrophosphate), and thiamine triphosphate (TTP) [9]. Inside cells, TDP is an important coenzyme in several biochemical processes, including carbohydrate and amino acid metabolism [10], [11], [12]. Additionally, several naturally occurring thiaminylated adenine nucleotides are found in bacteria and mammalian tissues [13], [14], [15].…”

Fatty acid profile and influence of oxythiamine on fatty acid content in Malassezia pachydermatis, Candida albicans and Saccharomyces cerevisiae

“…Oxythiamine also decreased the cell growth rate of yeast 18 and of M. pachydermatis 19 . It has also been shown that thiamine analogues can be phosphorylated inside a cell and interact with the active centres of thiamine‐dependent enzymes, decreasing their activity and affecting cell growth 20–23 . Decrease of cell growth rate by oxythiamine may be caused by changes in lipid metabolism, especially by the inhibition of multienzyme complexes that are involved in the distribution of acetyl‐CoA towards fatty acid synthesis 24 .…”