Pathways and Mechanisms in the Biogenesis of Novel Deoxysugars by Bacteria

Abstract

Science has long recognized the ubiquitously occurring deoxysugars as a novel and important class of carbohydrate, by virtue of the variety of potent and intriguing biological activities they exhibit. The study of the biosynthesis of these naturally vital molecules at a molecular level has received a great deal of attention in recent years, whether it be the well-established study of deoxyribonucleotide biosynthesis via ribonucleotide reductase or newer areas that include 3,6-dideoxyhexose construction and O antigen variation, as well as the emerging scrutiny of the biosynthesis of deoxysugar ligands of antibiotics and cardiac glycosides. This review attempts to update the various classes of deoxy, dideoxy, trideoxy, branched-chain, and amino sugars with respect to our current knowledge regarding the vast biological activities, genetics of formation, and molecular basis of their biosynthesis. In particular, the primary focus utilizes CDP-ascarylose biosynthesis, currently the best genetically and biochemically characterized dideoxysugar system, as a basis for comparison and postulation. This review helps display the elegant complexities of these essential natural saccharides and speculates upon tomorrow's potential applications.

Modification of glycopeptidolipids by an O-methyltransferase of Mycobacterium smegmatis a aThe GenBank accession number for the sequence determined in this work is AY138899.

“…Rhamnose is also required for glycosylation of GPLs in M. smegmatis, and genes for glucose-1-phosphate thymidylyltransferase (rmlA) and dTDP glucose 4,6-dehydrogenase (rmlB) occur in the GPL biosynthetic locus. Rhamnose and 6-dTal are derived from identical biosynthetic precursors, with two dTDP-dehydrorhamnose reductases having opposite stereospecificity providing either TDP-rhamnose or TDP-6-dTal (Liu & Thorson, 1994). The steps catalysed by RmlA and RmlB will therefore lead to synthesis of intermediates that could be converted to either of the sugars characteristic of GPLs.…”

“…Two genes in the GPL locus possibly encode the enzymes for the first two steps of rhamnose biosynthesis. The rmlA gene product is 92 % similar to RmlA of M. tuberculosis, which encodes glucose-1-phosphate thymidylyltransferase and has been shown to convert glucose 1-phosphate to dTDPglucose (Liu & Thorson, 1994 ;Ma et al, 1997). Several glucose-1-phosphate thymidylyltransferases have a conserved motif in the N-terminus which is also observed in the M. smegmatis RmlA polypeptide sequence (LAGGSGTRLHP) (Aguirrezabalaga et al, 2000 ;Merson-Davies et al, 1994 ;Steffensky et al, 2000).…”

The dnrM gene in Streptomyces peucetius contains a naturally occurring frameshift mutation that is suppressed by another locus outside of the daunorubicin-production gene cluster

“…The DNA sequence of a small portion of the 1.1 kb fragment amplified was determined. Its translated sequence is : VNVTVTGAAGQIGYALVTVIGAAGLIG YALQRT; residues in bold are highly conserved in TDP-D-glucose 4,6-dehydratases (Liu & Thorson, 1994). This sequence is not the same as that proposed for DnrM (Fig.…”

“…This irreversible reaction is an important first step in the activation of sugars for eventual transfer to other molecules (Liu & Thorson, 1994). Consequently, dnrL most likely provides this enzyme for daunosamine biosynthesis.…”

“…Thompson et al (1992) have partially purified a TDP-Dglucose 4,6-dehydratase from S. petleetins. The N-terminal sequence of their protein does not agree with that predicted for DnrM, although it does show some similarity to this family of dehydratases (Liu & Thorson, 1994). We synthesized degenerate oligodeoxynucleotides based on highly conserved regions at the N-terminus of the reported amino acid sequence (Thompson et al, 1992) and the reverse complement of the C-termini of such dehydratases (Liu & Thorson, 1994), then amplified by PCR the targeted region in the DNA from S. pezlcetias 29050.…”