Structure alteration of polyketides by recombinant DNA technology in producer organisms--prospects for the generation of novel pharmaceutical drugs.
Actinomycetes are gram-positive bacteria and commercially important microorganisms. They are producers of approximately two thirds of all bioactive compounds known and they produce a great variety of compounds which have clinical application on the basis of their activity against different kinds of organisms and cells as antibacterial (macrolides, avermectins), antitumor (anthracyclines, angucyclines, aureolic acid group) and also compounds showing immunosuppresant activity (rapamycin, FK506). Most of these clinically useful pharmaceuticals produced by actinomycetes belong to the polyketide family. Polyketides comprise a wide family of chemically diverse compounds, many of which have shown bioactivity. The development of recombinant DNA technology has opened a new and exciting field of research for the generation of new bioactive compounds through genetic manipulation of the biosynthetic pathways. Researchers in this area are trying to take advantage of the enormous capability of actinomycetes to produce pharmaceutically useful compounds in order to manipulate the different biosynthetic pathways and subsequently generate novel drugs. Combinatorial biosynthesis is now emerging as a powerful tool to generate novel families of compounds by interchanging secondary metabolism genes between bioactive producing actinomycetes. Novel compounds will be the consequence of the concerted action of enzymes from different, but related, biosynthetic pathways. Insertional inactivation of selected genes and tailoring modification may also produce novel compounds that can be useful pharmaceuticals or lead compounds for further chemical modification. This minireview will present the state of the art in this field showing the different polyketides biosynthetic pathways so far characterized and how the identified genes are being used to generate structural biodiversity. Emphasis will be made on the polyketide family including type I and type II polyketides.
Méndez
C
C
Departamento de Biología Funcional, Universidad de Oviedo, Spain.
Weitnauer
G
G
Bechthold
A
A
Salas
J A
JA
D000192:Actinomycetales / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D004274:DNA, Recombinant / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data
D000900:Anti-Bacterial Agents; D004274:DNA, Recombinant