Lincomycin

                         Chemical Formula: C₁₈H₃₄N₂O₆S

                         Molecular Weight: 406.538 g/mol

                         CAS #: 154-21-2

Systematic (IUPAC) Name: (4R)-N-[(1R,2R)-2-hydroxy-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyloxan-

2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide

Biosynthesis

Lincomycin is an antibiotic classified as a constituent of the lincosamide group, which typically feature a 6,8-dideoxy-6-aminooctose lincosamine [1]. In Lincomycin A, this sugar moiety (referred to as methylthiolincosamide) is linked via an amide bond to an amino acid derivative (referred to as propylhygric acid). Lincomycin biosynthesis occurs via a biphasic pathway producing propylproline and methylthiolincosamide followed by condensation of these subunits to N-demethyllincomycin and methyllation by S-adenosyl methionine to produce the antibiotic lincomycin.

In the biosynthesis of the amino acid moiety of lincomycin, tyrosine comprises seven of the nine carbons in the prophylhygric acid, while the remaining two carbons are added in reactions with S-adenosylmethionine [2,3,4,5]. Glucose is converted via glycolysis and the hexose monophosphate pathway to phosphoenolpyruvate and erythrose-4-phosphate, respectively, which are converted via the shikimate pathway to tyrosine and dihydroxyphenylalanine. Although the multistep conversion of dihydroxyphenylalanine to propylproline remains unknown, experiments involving accumulation of 1,2,3,6-tetradehydro-propylproline in mutants lacking a reductase requiring lincomycin cosynthetic factorsuggests a biosynthetic scheme that Kuo and coworkers have modified from Brahme et al. [4.5] to accomodate the remaining steps leading to propylproline [6,7].

The biosynthesis of the methythiolincosamide sugar moiety is still not entirely known, although two different pathways have been predicted [5,8]. One possible pathway proposes the C8 carbon framework of methythiolincosamide originates from the condensation of a pentose (C5) unit, stemming from either the hexose monophosphate or condensation through a transketolase reaction with glyceraldehyde-3-phosphate and sedoheptulose-7-phosphate, and a C3 unit, added throuhg a transaldolase reaction with sedoheptulose-7-phosphate. Once condensed, an octose (C8) unit is formed that can undergo isomerization to octose, dephosphorylation and reduction of the C8 carbon, transamination of 6-ketooctose, and thiomethylation of C1 to finally convert the octose unit to the methylthiolincosamide. A substantially different pathway for the formation of the methythiolincosamide proposes that its biosynthesis involves nucleotide activation followed by a series of modifications of dNTP-activated sugar intermediates. Eight genes, lmb-LMNZPOSQ, have been found to form a "sugar subcluster" which might be involved in this sugar metabolism [9].

Condensation of both the carboxyl group on the propylproline and the amine group of the methylthiolincosamide via an amide bond is catalyzed by N-Demethyllincomycin-synthetase and leads to the production of N-demethyllincomycin. N-Demethyllincomycin is then methylated by S-adenosylmethionine through N-Demethyllincomycin methyl transferase to form the final lincomycin product [10].

[1] Spizek, J, & Sp�ek. (2004). Lincomycin, cultivation of producing strains and biosynthesis. Applied microbiology and biotechnology, 63(5), 510-519.

[2] Argoudelis AD, Eble TE, Fox JA, Mason DJ (1969) Studies on the biosynthesis of lincomycin. IV. The origin of methyl groups. Biochemistry 8:3408–3411.

[3] Witz DF, Hessler EJ, Miller TL (1971) Bioconversion of tyrosine into the propylhygric acid moiety of lincomycin. Biochemistry 10:1128–1133.

[4] Brahme NM, Gonzalez JE, Mizsak S, Rolls JR, Hessler EJ, Hurley LH (1984a) Biosynthesis of the lincomycins. 2. Studies using stable isotopes on the biosynthesis of methylthiolincosaminide moiety of lincomycin A. J Am Chem Soc 106:7878–7883.

[5] Brahme NM, Gonzalez JE, Rolls JR, Hessler EJ, Mizsak S, Hurley LH (1984b) Biosynthesis of the lincomycins. 1. Studies using stable isotopes on the biosynthesis of the propyl- and ethyl-Lhygric aci  moieties of lincomycin A and B. J Am Chem Soc 106:7873–7878.

[6] Kuo MS, Yurek DA, Coats JH, Li GP (1989) Isolation and identification of 7,8-didemethyl-8-hydroxy-5-deazariboflavin, an unusual cosynthetic factor in streptomycetes, from Streptomyces lincolnensis. J Antibiot 42:475–478.

[7] Kuo MS, Yurek DA, Coats JH, Chung ST, Li GP (1992) Isolation and identification of 3-propylidiene acid, a biosynthetic precursor of lincomycin. J Antibiot 45:1773–1777.

[8] Peschke U, Schmidt H, Zhang HZ, Piepersberg W (1995) Molecular characterization of the lincomycin production gene cluster of Streptomyces lincolnensis 78–11. Mol Microbiol 16:1137–1156.

[9] Pissowotzki K, Mansouri K, Piepersberg W (1991) Genetics of streptomycin production in Streptomyces griseus: molecular structure and putative function of genes strELMB2N. Mol Gen

Genet 231:113–123.

[10] Patt TE, Horvath BA (1985) Isolation and characterization of Ndemethyllincomycin methyltransferase. In: Abstracts, 13th International Congress of Biochemistry, Amsterdam, The Netherlands, August 25–30 1985.