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, 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.

Biosynthesis of the Nuclear Factor of Activated T Cells Inhibitor NFAT-133 in Streptomyces pactum

“…To test the hypothesis, in-frame deletions were generated for the PKS genes of the BGC-1.2 locus in S. pactum Δ ptmTDQ . The Δ ptmTDQ strain was generated by inactivating the pactamycin aminotransferase gene ptmT in S. pactum Δ ptmDQ . − This strain produces NFAT-133 at the same level as the wild-type (∼25 mg L –1 ). The lack of ptmT in this mutant was expected to abolish the production of N , N -didemethyl-de-6MSA-7-deoxypactamycin (TM-102) and other pactamycin analogs, which coelute or have similar retention times with NFAT-133 in the HPLC. , The absence of TM-102 ( m / z 381 [M + H] + ) in this strain is also beneficial as its elimination overcomes an interference with the mass spectrometry analysis of a putative NFAT-133 analog, named TM-123 ( m / z 381 [M + Na] + ) (Figure b).…”

Identification and Biological Activity of NFAT-133 Congeners from Streptomyces pactum

“…S. pactum ATCC 27456 has been used as a model organism for the biosynthetic studies of the antitumor antibiotic pactamycin. ,− During the course of those studies, the potential of the strain to produce other bioactive natural products was recognized. Furthermore, inactivation of the NFAT-133 biosynthetic gene cluster in S. pactum ATCC 27456 Δ ptmTDQ , which does not produce pactamycin, ,, resulted in a mutant that also lacks the ability to produce NFAT-133 and a number of unknown minor metabolites .…”

The chemistry and biology of natural ribomimetics and related compounds

“…[106][107][108] Despite its potent biological activity, the development of pactamycin as a clinically useful drug was hampered by its broad-spectrum cytotoxicity. 109 In addition to pactamycin, a number of pactamycin analogues, e.g., 7-deoxypactamycin (99), pactamycate (100), pactalactam (101), and jogyamycin (102), have been isolated from various strains of S. pactum (Fig. 20).…”

“…24), which was found in the membrane lipids of a subset of thermoacidophilic archaea, e.g., Sulfolobus acidocaldarius. 135 This C-ribomimetic unit is ether-linked directly to the glycerol backbone of glycerol dibiphytanyl glycerol tetraethers (GDGTs) or related compounds, such as in calditolglycerocaldarchaeol (109), to form the components of the membrane lipids. These lipids are thought to be essential for archaebacteria to preserve their membrane functions under extreme conditions, such as high temperatures and strong acidity.…”