Abstract
While the cellular functions of the coenzyme thiamine (vitamin B1) diphosphate (ThDP) are well characterized, the triphosphorylated thiamine derivatives, thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), still represent an intriguing mystery. They are present, generally in small amounts, in nearly all organisms, bacteria, fungi, plants, and animals. The synthesis of ThTP seems to require ATP synthase by a mechanism similar to ATP synthesis. In E. coli, ThTP is synthesized during amino acid starvation, while in plants, its synthesis is dependent on photosynthetic processes. In E. coli, ThTP synthesis probably requires oxidation of pyruvate and may play a role at the interface between energy and amino acid metabolism. In animal cells, no mechanism of regulation is known. Cytosolic ThTP levels are controlled by a highly specific cytosolic thiamine triphosphatase (ThTPase), coded by thtpa, and belonging to the ubiquitous family of the triphosphate tunnel metalloenzymes (TTMs). While members of this protein family are found in nearly all living organisms, where they bind organic and inorganic triphosphates, ThTPase activity seems to be restricted to animals. In mammals, THTPA is ubiquitously expressed with probable post-transcriptional regulation. Much less is known about the recently discovered AThTP. In E. coli, AThTP is synthesized by a high molecular weight protein complex from ThDP and ATP or ADP in response to energy stress. A better understanding of these two thiamine derivatives will require the use of transgenic models.
Highlights
Thiamine is the precursor for thiamine diphosphate (ThDP), an essential coenzyme for many enzymatic reactions in prokaryotes and eukaryotes [1,2,3] (Figure 1).In animals, the main ThDP-dependent enzymes are the E1 subunits of 2-oxoacid dehydrogenase complexes and transketolase [4].These enzymes are essential in oxidative glucose metabolism, explaining why thiamine deficiency leads to severe lesions in particular in tissues with a high oxidative metabolism, such as brain and heart [5]
Different mechanisms were put forth concerning the synthesis of thiamine triphosphate (ThTP), among which the most straightforward is the transfer of a phosphate group from ATP to ThDP according to the reaction ThDP + ATP ThTP + ADP catalyzed by a ThDP:ATP phosphotransferase [30]
It is thought that in mammals, the reaction catalyzed by glutamate dehydrogenase (GDH) is favored in the catabolic sense. 2-Oxoglutarate can be either catabolically decarboxylated by 2-oxoglutarate dehydrogenase and continue through the citric cycle or anabolically funneled into amino acid metabolism by transamination
Summary
Thiamine (vitamin B1) is the precursor for thiamine diphosphate (ThDP), an essential coenzyme for many enzymatic reactions in prokaryotes and eukaryotes [1,2,3] (Figure 1). The main ThDP-dependent enzymes are the E1 subunits of 2-oxoacid (in particular, pyruvate and oxoglutarate) dehydrogenase complexes and transketolase [4]. These enzymes are essential in oxidative glucose metabolism, explaining why thiamine deficiency leads to severe lesions in particular in tissues with a high oxidative metabolism, such as brain and heart [5]. The aim of the present review is to discuss new data obtained on ThTP, AThTP, and their metabolizing enzymatic complexes (Figure 1)
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