Progress in aminocyclitol biosynthesis

Abstract

A stream of genetic and biochemical information available for the biosynthesis of aminocyclitols over the past few years has provided the foundation to study the modes of formation of this clinically important class of natural products. In addition to work on the identification and functional analysis of aminocyclitol biosynthetic gene clusters, a contingent of recent studies has focused on the detailed analysis of unique enzymatic and catalytic mechanisms inherent to these pathways. The results provide invaluable insights into the biochemical and molecular aspects of aminocyclitol biosynthesis and have revealed diverse and unique features of the pathways.

Figure 1

Biosynthetic pathways to various aminocyclitol natural products. MIPS, 1L-myo-inositol 1-phosphate synthase; DOIS, 2-deoxy-scyllo-inosose synthase; EVS, 2-epi-5-epi-valiolone synthase; DHQS, dehydroquinate synthase; aDHQS, aminodehydroquinate synthase.

Figure 2

Proposed pathways to various myo-inositol-derived aminoglycosides. The Hyg proteins are from the hygromycin pathway, the Spe and Spc proteins are from the spectinomycin pathway, and the Str and Sts proteins are from the streptomycin pathway.

Figure 3

Proposed biosynthetic pathway for the production of DOI-derived aminoglycosides. Multiple protein names above the arrows correspond to homologous enzymes from different pathways (Btr, from the butirosin pathway; Neo, from the neomycin pathway; and Gtm and Gac, from the gentamicin pathway) that catalyze the same reaction. Note that a number of these enzymes are used repetitively in the pathways.

Figure 4

Biosynthetic pathways to various C₇N-aminocyclitol-containing natural products. 2-epi-5-epi-Valiolone is the common intermediate involved in the biosynthesis of all C₇N-aminocylitol natural products.

Figure 5

Inactivation of the validamycin glycosyltransferase valG and the putative cyclitol reductase valN genes resulted in mutant strains that produced new aminocyclitol products. Bioconversion of the resulting pseudodisaccharides using recombinant glycosyltransferase ValG gave their respective glycosidal products.