Biosynthesis of the Lincomycins. 2. Studies Using Stable Isotopes on the Biosynthesis of Methylthiolincosaminide Moiety of Lincomycin A

Lincomycin is an antibiotic produced by Streptomyces lincolnensis and consists of a unique aminooctose moiety, α-methylthiolincosaminide (MTL), attached via an amide linkage to a propylhygric acid unit. The biosynthesis of the MTL moiety of lincomycin has been investigated by using both specifically carbon-13 labeled substrates and uniformly carbon-13 labeled D-glucose. In the latter case ¹³C-¹³C spin coupling patterns in lincomycin and MTL were used to determine those carbon atoms from glucose that remained intact during their conversion to the antibiotic. By combination of the biosynthetic information obtained from the ¹³C-¹³C spin coupling patterns with that from those carbon atoms in MTL which were enriched from carbon-13 specifically labeled molecules, conclusions can be drawn about likely pathways and intermediates between glucose and MTL. The C₈-carbon skeleton of MTL is assembled through condensation of a pentose unit (C₅) and a C₃ unit. The C₅ unit can be assembled in two ways. Either it is derived from glucose via the hexose monophosphate shunt (HMPS) as an intact unit or it is assembled from condensation of a C₃ unit (glyceraldehyde 3-phosphate) with a C₂-unit donor such as sedoheptulose 7-phosphate (SH7P) via a transketolase reaction. The C₃ unit, which combines with the C₅ unit, is likely contributed from a suitable donor molecule such as SH7P via a transaldolase reaction. Dependent upon the origin of the C₃-unit donor, this unit may consist either of an intact C₃ unit or a C₂ unit combined with a C₁ unit. The octase produced from condensation of a C₅ unit and a C₃ unit can then be converted by unexceptional means to MTL.