Thiamin (vitamin B1) biosynthesis and regulation: a rich source of antimicrobial drug targets?

Abstract

Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics.

Keywords: Mycobacterium tuberculosis; drug targets; riboswitch; thiamin biosynthesis.

Figure 1

The biosynthesis of thiamin in bacteria. The thiazole moiety of thiamin is derived from an oxidative condensation of 1-deoxy-D-xylulose 5-phosphate (DXP) (a), cysteine (b), and glycine or tyrosine (c). When the thiazole and pyrimidine moieties are formed, ThiE will coupled them to be thiamin monophosphate and followed by a phosphorylation step to give ThDP (d). Abbreviation: Dxs, 1-deoxy-D-xylulose 5-phosphate synthase; ThiF, adenyltransferase; ThiS, sulfur carrier protein; ThiG, thiazole synthase, ThiO, glycine oxidase; ThiH, thiazole synthase; ThiI, sulfur transferase; ThiC, hydroxymethyl pyrimidine synthase; ThiD, hydroxymethyl pyrimidine (phosphate) kinase; NifS, sulfur donor; TenI, transcriptional regulator TenI; IscS, cysteine desulfurase; ThiE, thiamin phosphate synthase; ThiL, thiamin phosphate kinase. This figure is modified from .

Figure 2

The salvage and transport pathways of thiamin in bacteria. Enzymes involved in the salvage of thiamin and its precursors are shown in saffron yellow background. The transport enzymes are shown in magenta background, primary and ATP-dependent transporters are in circles and rectangle, respectively. Abbreviations: ThiK, thiamin kinase; ThiM, thiazole kinase; ThiN, thiamin pyrophosphokinase.

Figure 3

The structure of inhibitors. Selected inhibitors of ThDP-dependent enzymes, Dxs and ThiE are shown as a, b, and c, respectively.

Figure 4

Regulatory mechanism of ThDP riboswitches and the structure of ThDP and Pyrithiamin diphosphate. (Top) When ThDP is at lower concentration during the synthesis of the 5'-UTR, the ThDP riboswitch would not inhibit the expression of ThDP biosynthetic genes (a, b, c, left), then “gene on”. When ThDP is at higher concentration, depending on the the expression platform, the ThDP riboswitch would fold to a transcription terminator (a), a suppressor of translation initiation (b), or a modulator of splicing (c), it is the “gene off” state (a, b, c, right). (Bottom) The structure of ThDP and pyrithiamin diphosphate. The initiation codon and Shine-Dalgarno (SD) sequence are shaded green brown, complementary sequences and their alternate base pairing are shown in green. The red and blue represent ThDP and Mg²⁺ ions, respectively. This figure is modified from , .