The secondary metabolite pactamycin with potential for pharmaceutical applications: biosynthesis and regulation

Abstract

The antitumor antibiotic pactamycin is a highly substituted aminocyclopentitol-derived secondary metabolite produced by the soil bacterium Streptomyces pactum. It has exhibited potent antibacterial, antitumor, antiviral, and antiprotozoal activities. Despite its outstanding biological activities, the complex chemical structure and broad-spectrum toxicity have hampered its development as a therapeutic, limiting its contribution to biomedical science to a role as a molecular probe for ribosomal function. However, a detailed understanding of its biosynthesis and how the biosynthesis is regulated has made it possible to tactically design and produce new pactamycin analogues, some of which have shown improved pharmacological properties. This mini-review describes the biosynthesis, regulation, engineered production, and biological activities of pactamycin and its congeners. It also highlights the suitability of biosynthetic methods as a feasible approach to generate new analogues of complex natural products and underscores the importance of utilizing biosynthetic enzymes as tools for chemoenzymatic production of structurally diverse bioactive compounds.

Keywords: Antibiotics; Biosynthesis; Pactamycin; Regulation; Streptomyces pactum.

Figure 1.

Chemical structures of pactamycin and its congeners

Figure 2.

Biosynthetic origin of pactamycin. The aminocyclopentitol core is derived from glucose, presumably via N-acetylglucosamine; the 3-aminoacetophenone moiety is derived from the shikimate pathway; and the 6-methylsalicylyl moiety is derived from four molecules of acetate by an iterative type I polyketide synthase enzyme. The methyl groups and C-7 are derived from methionine.

Figure 3.

Biosynthesis of 3-aminobenzoic acid and proposed pathways to 3-aminoacetophenone. A. Formation of a β-ketoacyl intermediate by Claisen condensation involving acetyl-CoA. B. Formation of a β-ketoacyl intermediate by Claisen condensation involving discrete PKS proteins.

Figure 4.

Proposed mode of formation of the 3-aminocyclopentitol ring.

Figure 5.

Tailoring steps in pactamycin biosynthesis. Many tailoring enzymes in pactamycin biosynthesis have relaxed substrate specificity.

Figure 6.

The biosynthesis and transfer of the 6-methylsalicylyl moiety. A. 6-methylsalicylyl moiety is produced by the iterative type I PKS PtmQ and transferred to de-6MSA-pactamycin by a KAS III-like enzyme PtmR. B. PtmR recognizes various N-acetylcysteamine thioesters as substrates to produce a suite of pactamycin analogues.