Polyketides

Abstract

Polyketides are a large group of secondary metabolites of varied structure with carbon chains formed by decarboxylative addition of malonyl thioesters to a starter unit. Some are useful drugs, others are toxic or carcinogenic; genetic engineering may lead to new polyketide drugs.

Keywords: combinatorial biosynthesis; genetic engineering; polyacetates; polyketides; secondary metabolites

Figure 1.

The polyacetate hypothesis. In general, in all figures, methyl groups are represented by a line without the addition of CH3. The figure shows the possible cyclizations of tetraacetic acid assumed to be formed by condensation of four acetyl units. Aldol type condensations, –CH2– + –CO–, are shown as A, leading to orsellinic acid [I], or 6‐methylsalicylic acid (6‐MSA) [II]. Acyl‐type condensations, –CH2– + –CO–OH, are shown as B, leading to phloroacetophenone [III]. Acyl cyclizations –CO– + –CO–, are shown as C leading to a pyrone [IV] or as D leading to tetraacetic acid lactone [V]. Note that orsellinic acid formation requires only loss of one H2O, but 6‐MSA formation requires the reduction, –CO– → –CHOH–, and loss of two H2O. With the possible exception of [IV] all structures are natural products. Phloroacetophenone [III] is an intermediate in usnic acid biosynthesis and its 2,4‐dimethyl ether is xanthoxylin. The solid circles (•) represent 14C introduced from [1‐14C]acetate and for simplicity are only shown for 6‐MSA (four labelled positions). With [1,3‐14C2]malonate the ring carbon attached to CH3 is not labelled so there are only three labelled positions. Similar labelling patterns (not shown) would be obtained for the other metabolites.

Figure 2.

Diketide biosynthesis. AC = acetyl‐CoA carboxylase, AT = acyltransferase, KS = ketosynthase, CoA = coenzyme A, ACP = acyl carrier protein. For description, see text. The diketide is oxobutyryl‐ACP, CH3–CO–CH2–CO–S–ACP.

Figure 3.

Orsellinic acid biosynthesis. The top line shows the further elongation of a diketide to a triketide by the mechanism of Figure . Further elongation leads to the tetraketide‐ACP structure. Aromatization to orsellinic acid requires loss of a single H2O (see arrows) and a tautomeric rearrangement. ACP = acyl carrier protein.

Figure 4.

Biosynthesis of 4‐(2‐butenyl)‐4‐methyl‐L‐threonine [VI]. KS = ketosynthase, KR = ketoreductase, DH = dehydratase, ER = enoyl reductase, SAM implies methylation from S‐adenosylmethionine (SAM). The dotted and wedge shaped bonds are the usual stereochemical conventions for below and above the paper plane respectively. An 8‐carbon chain is produced from one acetate and three malonate units by three ‘cycles’ of elongation; an additional carbon is added by C‐methylation. The activities used in the three cycles are as follows: cycle 1, KS, KR, DH; cycle 2, KS, C‐methylation, KR, DH, ER; Cycle 3, KS, KR. At some point the C2 amino group is introduced, presumably by transamination to a carbonyl structure.

Figure 5.

Tylactone biosynthesis. The molecule shown is tylactone itself. A = acetate, B = butyrate, P = propionate; the carbon skeletons of these units are shown by thickened bonds with the carboxyl terminus indicated as •. To form the tylosin aglycone, the original CH3 from butyrate becomes CHO. The indicated CH3, from propionate becomes CH2OH, and adds a monosaccharide unit. The OH marked as ⋄ adds a disaccharide unit.

Figure 6.

Actinorhodin biosynthesis. In the description following: ARO = aromatase; CYC = cyclase; CLF = chain length factor; KS = ketosynthase; E = enzyme; PKS = polyketide synthase; ACP = acyl carrier protein; KR = ketoreductase. Genes and activities as follows: (1), actI, minimal PKS; three open reading frames in actI constitute the so‐called ‘minimal PKS’ (KS, CLF, ACP) directing the first ring cyclization. Note the loss of seven CO2 (not shown) and that (1) is assigned to two reaction steps. (2) = actIII, KR (a reducing agent is required, probably NADPH). (3) = act VII, ARO; loss of two H2O converts first ring to an aromatic structure. (4) = actIV, CYC; a second ring is formed. (5) = actVI, actVA, actVB; these genes produce ‘tailoring’ enzymes to complete formation of the dimeric actinorhodin molecule.

Figure 7.

6‐Deoxyerythronolide B biosynthesis. DEBS = deoxyerythronolide B synthase, M = module, TE = terminal thioesterase; other abbreviations as before – see earlier figures. The acyl carrier protein (ACP) domain is represented by S for its thiol group. This metabolite is an example of a polypropionate structure. The process begins with the loading of a single propionyl unit and the figure shows the structure at the end of the reactions catalysed by the components of each module. In the final product, all of the CH3 and OH substituents have a defined chirality.

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References

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Further Reading

Bentley R and Bennett JW (1999) Constructing polyketides: from Collie to combinatorial biosynthesis. Annual Review of Microbiology 53: 411–446.

Cane DE (ed.) (1997) Polyketide and nonribosomal polypeptide biosynthesis. Chemical Reviews 97: 2463–2705. (This ‘Special Thematic Issue’ contains 10 articles on polyketides by leaders in this field of research.)

Hutchinson CR and Fujii I (1995) Polyketide synthase gene manipulation: a structure–function approach in engineering novel antibiotics. Annual Review of Microbiology 49: 201–238.

Khosla C, Gokhale RS, Jacobsen JR and Cane DE (1999) Tolerance and specificity of polyketide synthases. Annual Review of Biochemistry 68: 219–253.

O’Hagan D (1991) The Polyketide Metabolites. New York: Ellis Horwood.

Rawlings BJ (1997) Biosynthesis of polyketides. Natural Product Reports 14: 523–556. (See also related articles in earlier volumes of this series.)

Strohl WR (ed.) (1997) Biotechnology of Antibiotics, 2nd edn. New York: Marcel Dekker.

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How to Cite close
Bentley, Ronald(Apr 2001) Polyketides. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0002343]