3-Ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis

Abstract

The 3-ketoacyl-ACP synthase (KAS) III proteins are one of the most abundant enzymes in nature, as they are involved in the biosynthesis of fatty acids and natural products. KAS III enzymes catalyse a carbon-carbon bond formation reaction that involves the α-carbon of a thioester and the carbonyl carbon of another thioester. In addition to the typical KAS III enzymes involved in fatty acid and polyketide biosynthesis, there are proteins homologous to KAS III enzymes that catalyse reactions that are different from that of the traditional KAS III enzymes. Those include enzymes that are responsible for a head-to-head condensation reaction, the formation of acetoacetyl-CoA in mevalonate biosynthesis, tailoring processes via C-O bond formation or esterification, as well as amide formation. This review article highlights the diverse reactions catalysed by this class of enzymes and their role in natural product biosynthesis.

Fig. 1. Catalytic function of KAS III enzymes in fatty acid biosynthesis.

Fig. 2. Crystal structure of EcFabH. a) Ribbon diagram of FabH from E. coli (PDB ; 3IL9) showing the homodimeric structure of FabH observed in the crystal. The different monomers are coloured teal and violet respectively. b) Zoomed in view of active site of EcFabH showing the Cys₁₁₂ (as a cysteine dioxide resulting from oxidation)-His₂₄₄-Asn₂₇₄ catalytic triad. The carbon atoms are coloured cyan, oxygen atoms are coloured red, nitrogen atoms are coloured blue, and sulphur atoms are coloured yellow. The figure was created in PyMol.

Fig. 3. Chemical structures of type II PKS-derived natural products.

Fig. 4. Chemical structures of non-type II PKS-derived natural products.

Fig. 5. KAS III proteins are involved in the biosynthesis of alkylmalonyl-CoA. a) Formation of allylmalonyl-CoA in FK506 producing strains. b) Formation of butylmalonyl-CoA in reveromycin producing Streptomyces.

Fig. 6. Biosynthetic pathway to alkylquinolones in Pseudomonas spp.

Fig. 7. Chemical structures of natural products formed through a head-to-head condensation mechanism catalysed by KAS III-like enzymes.

Fig. 8. Proposed head-to-head condensation mechanisms catalysed by KAS III-like enzymes. a) Formation of the α-pyrone moiety in corallopyronin A biosynthesis. b) Formation of the α-pyrone moiety in photopyrone D biosynthesis.

Fig. 9. Chemical structures of tetronate-containing natural products.

Fig. 10. Proposed mode of formation of the tetronate moiety in RK-682.

Fig. 11. Formation of acetoacetyl-CoA and its analogues by KAS III-like enzymes.

Fig. 12. Esterification reactions catalysed by KAS III-like enzymes.

Fig. 13. Crystal structures of DpsC and CerJ. a) Aligned ribbon diagrams of CerJ (cyan, PDB 3S3L) and DpsC (violet, PDB ; 5WGC) showing the high degree of tertiary structure similarity between these two enzymes. b) A zoomed in picture of the catalytic triad residues from panel a demonstrating the similarity in active site architecture between DpsC (carbon atoms are coloured violet) and CerJ (carbon atoms are coloured cyan). In both structures, oxygen atoms are coloured red, nitrogen atoms are coloured blue and sulphur atoms are coloured yellow. The catalytic triad of CerJ is Cys-his-asp while in DpsC it is Ser-his-asp. In DpsC, the active site Ser is trapped as the propionyl ester. The figure was created in PyMol.

Fig. 14. Amide formation by a KAS III-like enzyme.

Risa Nofiani

Benjamin Philmus

Yosi Nindita

Taifo Mahmud