It is remarkable that 60 years after the discovery and synthesis of Vitamin B1 and of Vitamin B6, and the recognition of their nutritional importance, and 30 years after the elucidation of their biochemical function, knowledge of their biosynthesis is still incomplete. The major source of the carbons of each of the two Vitamins is glucose. The routes to the two Vitamins in a bacterium, Escherichia coli, are becoming clear, but questions remain. A different, as yet undefined, route to B1 operates in yeast. The path to B6 in yeast is unknown. The two major objectives of the present proposal are (i) the elucidation of the steps leading to the two Vitamins in yeast, and a critical examination of the question whether there exists a precursor-product relationship between the two Vitamins; and (ii) final clarification of the status of several intermediates of the metabolic routes to the two Vitamins in E.coli. Vitamin B1: Incorporation studies with multiply 13C labeled samples of glucose and ribose will define the mode of entry of a C1 and a C2 unit, both derived from ribose, into the pyrimidine moiety in B1 in E. coli, and will determine the precise origin of the glucose-derived carbon atoms of thiamin in yeast. Most of the required multiply 13C labeled samples will have to be synthesized since they are not available commercially. Vitamin B6: The origin of B6 in yeasts is unknown. It cannot be assumed a priori that the route to B6 in yeast is identical with that in E.coli, since other Vitamins (e.g., thiamin, niacin) have distinct modes of origin in prokaryotes and eukaryotes. Two questions will be answered: Is the mode of biosynthesis of B6 in yeast the same or different from that in E. coli. (ii) In yeast is Vitamin B6 a precursor of the pyrimidine unit of Vitamin B1, as has recently been suggested. Experiments with multiply 13 C-labeled substrates, followed by analysis by high field 13C NMR, will provide the evidence which will serve to answer these questions. By definition, Vitamins are not synthesized in mammals. It is now evident that the primary precursor of B1 and B6 are glucose and other common metabolites. It is the long term objective of the study to identify the step in each pathway which is blocked in human tissues, thereby making the compounds Vitamins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Mcmaster University
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L8 3-Z5
Zeidler, Johannes; Sayer, Brian G; Spenser, Ian D (2003) Biosynthesis of vitamin B1 in yeast. Derivation of the pyrimidine unit from pyridoxine and histidine. Intermediacy of urocanic acid. J Am Chem Soc 125:13094-105
Zeidler, Johannes; Gupta, Ram Nath; Sayer, Brian G et al. (2003) Biosynthesis of Vitamin B(6) in yeast. Incorporation pattern of trioses. J Org Chem 68:3486-93
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