Pyridine rings, biosynthesis

Even though E. coli is a very well-studied bacterium, many interesting mechanistic problems in cofactor biosynthesis in this organism remain unsolved. The mechanisms for the formation of the nicotinamide ring of NAD, the pyridine ring of pyridoxal, the pterin system of molybdopterin, and the thiazole and pyrimidine rings of thiamin are unknown. The sulfur transfer chemistry involved in the biosynthesis of lipoic acid, biotin, thiamin and molybdopterin is not yet understood. The formation of the isopentenylpyrophosphate precursor to the prenyl side chain of ubiquinone and menaquinone does not occur by the mevalonate pathway. None of the enzymes involved in this alternative terpene biosynthetic pathway have been characterized. The aim of this review is to focus attention on these unsolved mechanistic problems. 

The pyridine ring plays a key role in several biological processes, most notably in the oxidation/reduction coenzyme nicotine adenine dinucleotide (NADP) the vitamin niacin (or the corresponding acid) is required for its biosynthesis. Pyridoxine (vitamin Bg) plays a key role as the coenzyme in transaminases. Nicotine, a highly toxic alkaloid, is the major active component in tobacco, and the most addictive drug known. ... 

Lysine has also a role in the biosynthesis of Nicotiana alkaloids, e.g., anabasine, in which beside nicotinic acid, the precursor of pyridine ring, lysine formed the piperidine core. 

The origins of the skeletal fragments of 6.19), 6.20), and 6.21) not accounted for by lysine (and A -piperideine) are as follows. The C3 side-chain in A -methylpelletierine 6.19) has its origins in acetate plausibly via acetoacetate [9]. The side-chain of sedamine 6.21), on the other hand, derives from phenylalanine, probably by way of its deamination product, cinnamic acid [10, 11]. Benzoylacetic acid, a normal in vivo transformation product of cinnamic acid, may also reasonably be included in the pathway to this alkaloid, as it is in, e.g., the biosynthesis of lobeline 6.34) and of phenanthroindolizidine alkaloids (see Section 6.2.2). The pyridine ring of anabasine 6.20) arises from nicotinic acid [14] by way presumably of 6.5) (cf nicotine. Section 6.2.2). The acid precursors (see Scheme 6.6) for 6.19), 6.20) and 6.21), have in common an electron-donating functionality (Scheme 6.7) which may react with A -piperideine 6.18), possibly with concommitant decarboxylation, to give the alkaloids (cf fatty acid biosynthesis. Section 1.1.2). 

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Natural products biosynthesis, 1, 83-109 fused oxirane rings, 7, 192 fused thiirane rings, 7, 192-193 as insecticides, 1, 198 nomenclature, 1, 28-31 oxiranes, 7, 120 as pharmaceuticals, 1, I46-I56 pyridine derivatives... 

Thieno[2,3-. ]pyridine derivatives, 155, can be successfully used as replacements for the hexahydronaphthalene ring found in naturally occurring 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors <2001BML1285>. These compounds also display significant inhibition of cholesterol biosynthesis in vivo. 

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