Thiamine, precursors

In bacteria, the pyrimidine precursor 38 is derived from 5-aminoimidazole ribotide (37), an intermediate of the basic branch of purine biosynthesis, which supplies all carbon atoms for 38 by a complex rearrangement reaction (the fate of the individual carbon atoms is indicated by Greek letters in Fig. 4). In yeasts, a totally unrelated reaction sequence uses carbon atoms from vitamin Be (39) that are indicated by roman letters in Fig. 4 for the assembly of the thiamine precursor 38,... 

It is not entirely clear why a mutation in pur A creates a selection for a secondary mutation in purR. The answer may be related to the marked difference between Class I and Class II mutants in their growth response to exogenous adenine. The growth of wild-type Salmonella is inhibited by adenine in the medium (125). The inhibition can be prevented by thiamine or its pjrrimidine moiety probably because elevated levels of adenine repress the de novo pathway, thus reducing the concentration of aminoimidazole ribotide which is a thiamine precursor (126). This notion was consistent with the observation that Class I strains are markedly sensitive to adenine inhibition of growth rate under conditions where Class II strains are completely resistant. 

Thiazolium derivatives unsubstituted at the 2-position (35) are potentially interesting precursors of A-4-thiazoline-2-thiones and A-4-thiazoline-2-ones. Compound 35 in basic medium undergoes proton abstraction leading to the very active nucleophilic species 36a and 36b (Scheme 16) (43-46). Special interest has been focused upon the reactivity of 36a and 36b because they are considered as the reactive species of the thiamine action in some biochemical reaction, and as catalysts for several condensation reactions (47-50). 

Naturally occurring quaternary ammonium compounds have been reviewed (179). Many types of aliphatic, heterocycHc, and aromatic derived quaternary ammonium compounds are produced both in plants and invertebrates. Examples include thiamine (vitamin B ) (4) (see Vitamins) choline (qv) [62-49-7] (5) and acetylcholine (6). These have numerous biochemical functions. Several quaternaries are precursors for active metaboUtes. 

Over 250 analogues of the B vitamers have been reported (11,100). Nearly all have low vitamin B activity and some show antagonism. Among these are the 4-deshydroxy analogue, pyridoxine 4-ethers, and 4-amino-5-hydroxymeth5i-2-methyipyrimidine, a biosynthetic precursor to thiamine. StmcturaHy unrelated antagonists include dmgs such as isoniazid, cycloserine, and penicillamine, which are known to bind to pyridoxal enzyme active sites (4). 

The pathways for thiamine biosynthesis have been elucidated only partiy. Thiamine pyrophosphate is made universally from the precursors 4-amino-5-hydroxymethyl-2-methylpytimidinepyrophosphate [841-01-0] (47) and 4-methyl-5-(2-hydroxyethyl)thiazolephosphate [3269-79-2] (48), but there appear to be different pathways ia the eadier steps. In bacteria, the early steps of the pyrimidine biosynthesis are same as those of purine nucleotide biosynthesis, 5-Aminoimidazole ribotide [41535-66-4] (AIR) (49) appears to be the sole and last common iatermediate ultimately the elements are suppHed by glycine, formate, and ribose. AIR is rearranged in a complex manner to the pyrimidine by an as-yet undetermined mechanism. In yeasts, the pathway to the pyrimidine is less well understood and maybe different (74—83) (Fig. 9). 

As shown in Eigure 18.17, thiamine is composed of a substituted thiazole ring joined to a substituted pyrimidine by a methylene bridge. It is the precursor of thiamine pyrophosphate (TPP), a coenzyme involved in reactions of carbo-... 

Still more confusion plagued early researches, when it was not realized that the biosynthetic routes to thiamine in prokaryotes and eukaryotes are quite different, a fact not expected at the outset. Thus, evidence collected from the study of yeast could not be transposed to bacteria, and vice-versa. For instance, formate is a most efficient precursor of one of the carbon atoms of the pyrimidine part of thiamine (pyramine), both in yeasts and enterobacteria, but incorporates at C-2 in bacteria and at C-4 in yeast. However, as is briefly covered in Section VIII, this dichotomy of pathways might have a deep significance in the perspective of biochemical evolution during primitive life on Earth. 

Biosynthesis of Thiamine Diphosphate from Thiazole and Pyrimidine Precursors... 

Scheme 10.—The assembly of precursors in the building of the thiamine thiazole in Enterobacteria.

An extract from the soluble stromal proteins of purified and intact spinach-leaf chloroplasts was prepared by lysis of the cells in buffer, centrifugation of the suspension of broken cells, and concentration of the supernatant with removal of insoluble material. This extract contained all of the enzymes involved in the condensation of the cyclic moieties of thiamine, thiazole, and pyramine. Thus, the synthesis of thiamine in this extract following the addition of pyramine and putative precursors was a proof that the system had the possibility of building the thiazole. It was found that L-tyrosine was the donor of the C-2 carbon atom of thiazole, as in E. coli. Also, as in E. coli cells, addition of 1 -deoxy-D-f/irco-pen-tulose permitted synthesis of the thiamine structure. The relevant enzymes were localized by gel filtration in a fraction covering the 50- to 350-kDa molecular-mass range. This fraction was able to catalyze the formation of the thiazole moiety of thiamine from 0.1 -mM 1-deoxy-D-t/ireo-pentulose at the rate of 220 pmol per mg of protein per hour, in the presence of ATP and Mg2+. 

Scheme 15.—Pyruvate and glucose (or glycerol) as precursors of the five-carbon chain of the thia-zole of thiamine in E. coli.

Nevertheless, the isolation of these metabolites was interesting in two respects. First, the structure of the thiazole glycol stimulated the research of functionalized carbohydrate chains as precursors of thiazole. Second, the thiazolecar-boxylic acid 40 can be secreted by derepressed cells in relatively high amounts, 0.24 nmol per mg of dried cells, which is nearly half the amount of synthesized thiamine. The presence of this free thiazolic derivative in the cells contrasts with... 

IV. A Pentulose or Pentulose Derivative as the Precursor of the Five-carbon Chain of the Thiazole of Thiamine in Yeasts... 

Escherichia coli Adenine and adenosine are inhibitory74 and the synthesis of thiamine can be derepressed by culture in their presence.13,75 adth- Mutants are known.76 [l4C]Formate incorporates at C-2 of pyramine without dilution of molar activity. Glycine labeled with stable isotopes was fed to E. coli and the pyramine was analyzed by mass spectrometry. The two carbon atoms of glycine separated during the biosynthesis. The carboxyl was found12 at C-4, and the C-N fragment was the precursor of C-6-N-1. In conclusion, it is beyond doubt that pyramine synthesis follows the AIR pathway in E. coli. 

Thiamine diphosphate, biosynthesis, from thiazole and pyrimidine precursors, 269-271... 

At the beginning of the MEP pathway, the glycolytic products, pyruvate and D-glyceraldehyde (GAP), are condensed in a transketolase reaction to deoxy-xylulose phosphate (DXP) by the deoxy-xylulose phosphate synthase (DXS) enzyme. DXP is the precursor for other pathways leading to pyridoxal and thiamine. 

Sprenger, G.A. et al.. Identification of a thiamin-dependent synthase in Escherichia coli required for the formation of the 1-deoxy-D-xylulose 5-phosphate precursor to isoprenoids, thiamin, and pyridoxol, Proc. Natl. Acad Sci. USA 94, 12857, 1997. Lange, B.M. et al., A family of transketolases that directs isoprenoid biosynthesis via a mevalonate-independent pathway, Proc. Natl. Acad Sci. USA 95, 2100, 1998. Lois, L.M. et al., Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-1- deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis, Proc. Natl. Acad. Sci. USA 95, 2105, 1998. 

Vitamin Bi, or thiamine, is a precursor to thiamine pyrophosphate, an essential coenzyme for several enzymes. Beriberi is a vitamin Bi deficiency disease. 

Vitamin B thiamine the precursor to the coenzyme thiamine pyrophosphate. 

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