page_title: Curcumin synthase
section_title: Mechanism
hierarchical_section_title: Curcumin synthase / Mechanism
caption_attribution_description: English: Original work using ChemBioDraw. Based upon the mechanism elucidated in "Structural and Biochemical Elucidation of Mechanism for Decarboxylative Condensation of β-Keto Acid by Curcumin Synthase" doi:10.1074/jbc.M110.196279
context_page_description: Curcumin synthase categorizes three enzyme isoforms, type III polyketide synthases present in the leaves and rhizome of the turmeric plant that synthesize curcumin. CURS1-3 are responsible for the hydrolysis of feruloyldiketide-CoA, previously produced in the curcuminoid pathway, and a decarboxylative condensation reaction that together comprise one of the final steps in the synthesis pathway for curcumin, demethoxycurcumin, and bisdemethoxycurcumin, the compounds that give turmeric both its distinctive yellow color, and traditional medical benefits. CURS should not be confused with Curcuminoid Synthase, which catalyzes the one-pot synthesis of bisdemethoxycurcumin in Oryza sativa.
context_section_description: Each CURS catalyzes the reactions necessary to convert a feruloyldiketide-CoA into a curcuminoid, but the three isoforms have preferred starter substrates and products.  CURS1 converts feruloyldiketide-CoA esters into curcumin using feruloyl-CoA exclusively as a starter substrate. CURS2 produces both curcumin and demethoxycurcumin, favoring feruloyl-CoA as a starter, and CURS3 produces curcumin, demethoxycurcumin, and bisdemethoxycurcumin from either feruloyl-CoA or 4-coumaroyl-CoA as the starter substrate. The fact that preferences of starter substrates vary between the three CURS is corroborated by carbon labeling studies confirming the incorporation of a variety of starter substrates into curcuminoid products in C. longa.
  Only the mechanism of CURS1 has been elucidated.  In the first step, the feruloyl moiety of feruloyl-CoA is transferred to Cys (164) followed by feruloyldiketide-CoA entering the CoA binding tunnel and being hydrolyzed through an unknown mechanism to a β-keto acid.  The acid is then used as an extender substrate in the catalytic triad, where it undergoes decarboxylative condensation with the feruloyl moiety on Cys (164). This mechanism is thought to be identical to that of the decarboxylative condensation of malonyl-CoA in other type III PKSs. The hydrolysis of the diketide has been shown to be the rate-limiting step of the enzyme.
  It was previously hypothesized that the curcumoid pathway employed two cinnamoyl-CoAs and one malonyl-CoA, but this was suggested against by the absence of a necessary intermediate such a pathway (bisdeshydroxybisdesmethoxycurcumin), strengthening evidence for feruloyl-CoA or 4-coumaroyl-CoA as starter substrate in CURS.
caption: The Proposed Mechanism of CURS1-Original work using ChemBioDraw. Based upon the mechanism elucidated in doi:10.1074/jbc.M110.196279
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