The genes and enzymes involved in the biosynthesis of thiamin and thiamin diphosphate in yeasts

Abstract

Thiamin (vitamin B1) is an essential molecule for all living organisms. Its major biologically active derivative is thiamin diphosphate, which serves as a cofactor for several enzymes involved in carbohydrate and amino acid metabolism. Important new functions for thiamin and its phosphate esters have recently been suggested, e.g. in gene expression regulation by influencing mRNA structure, in DNA repair after UV illumination, and in the protection of some organelles against reactive oxygen species. Unlike higher animals, which rely on nutritional thiamin intake, yeasts can synthesize thiamin de novo. The biosynthesis pathways include the separate synthesis of two precursors, 4-amino -5-hydroxymethyl-2-methylpyrimidine diphosphate and 5-(2-hydroxyethyl)-4-methylthiazole phosphate, which are then condensed into thiamin monophosphate. Additionally, yeasts evolved salvage mechanisms to utilize thiamin and its dephosphorylated late precursors, 4-amino-5-hydroxymethyl-2-methylpyrimidine and 5-(2-hydroxyethyl)-4-methylthiazole, from the environment. The current state of knowledge on the discrete steps of thiamin biosynthesis in yeasts is far from satisfactory; many intermediates are postulated only by analogy to the much better understood biosynthesis process in bacteria. On the other hand, the genetic mechanisms regulating thiamin biosynthesis in yeasts are currently under extensive exploration. Only recently, the structures of some of the yeast enzymes involved in thiamin biosynthesis, such as thiamin diphosphokinase and thiazole synthase, were determined at the atomic resolution, and mechanistic proposals for the catalysis of particular biosynthetic steps started to emerge.

Thiamine Biosynthesis in Saccharomyces cerevisiae Is Regulated by the NAD+-Dependent Histone Deacetylase Hst1

“…Its synthesis has been well characterized in bacteria, but knowledge of the early steps of de novo synthesis in yeast is less complete (25). Yeast first separately synthesizes two precursors, 5-(2-hydroxyethyl)-4-methylthiazole phosphate (HET-P) and 4-amino-5-hydroxymethyl-2-methylpyrimidine diphosphate (HMP-PP) through poorly understood mechanisms.…”

“…HMP-PP is synthesized in yeast cells from histidine and pyridoxal-5-phosphate (PLP; vitamin B6), thus providing a link between the synthesis pathways for these two soluble B vitamins. The substrates for HET-P synthesis include cysteine, glycine, and D-pentulose-5-phosphate (25). More recently, synthesis of the HET-P moiety was shown to also proceed through an advanced intermediate generated by the Thi4 protein in a reaction that consumes NAD ϩ as a substrate, releasing nicotinamide (NAM) as a by-product (12).…”

THI1, a protein involved in the biosynthesis of thiamin in Arabidopsis thaliana: Structural analysis of THI1(A140V) mutant

“…It was discovered in 1911 by Casimir Funk, isolated in 1932 from yeast and synthesized in 1935 [2]. Though occurring in all living cells, only prokaryotes and a few eukaryotes, such as fungi and plants, are able to de novo synthesize thiamine [3,4]. Because thiamine-dependent enzymes are crucial for central metabolic pathways, changes in thiamine regulation can affect many different processes.…”

“…Labeling studies in S. cerevisiae have demonstrated that the thiamine-thiazole is synthesized from an unidentified five-carbon carbohydrate, glycine, and cysteine [12]. This biosynthesis has not yet been reproduced in vitro, but a metabolomic study has recently proposed NAD + (nicotinamide adenine dinucleotide) as the early source of a five-carbon carbohydrate and the advanced intermediate as an ADP adduct of 5-(2-hydroxyethyl)-4-methylthiazole-2-carboxylic acid [4,14]. The gene encoding THI1 protein was originally cloned due to its capacity to complement Escherichia coli mutant line BW535 (xth, nfo and nth genes), which is defective in DNA base excision repair pathways [13].…”

ThiN as a Versatile Domain of Transcriptional Repressors and Catalytic Enzymes of Thiamine Biosynthesis

“…These moieties are synthesized by two separate branches regardless of the organism and require about 16 genes for their de novo biosynthesis (1,2) (Fig. 1A).…”