HC-toxin is a cyclic tetrapeptide of structure cyclo(D-Pro-L-Ala-D-Ala-L-Aeo), where Aeo stands for 2-amino-9,10-epoxi-8-oxodecanoic
acid. It is a determinant of specificity and virulence in the interaction between the producing fungus, Cochliobolus carbonum, and its host, maize.
HC-toxin qualifies as one of the few microbial secondary metabolites whose ecological function in nature is understood. Reaction to C. carbonum and to
HC-toxin is controlled in maize by the Hm1 and Hm2 loci. These loci encode
HC-toxin reductase, which detoxifies
HC-toxin by reducing the 8-carbonyl group of Aeo.
HC-toxin is an inhibitor of
histone deacetylases (HDACs) in many organisms, including plants, insects, and mammals, but why inhibition of HDACs during
infection by C. carbonum leads to disease is not understood. The genes for
HC-toxin biosynthesis (collectively known as the TOX2 locus) are loosely clustered over >500 kb in C. carbonum. All of the known TOX2 genes are present in multiple, functional copies and are absent from natural toxin non-producing isolates. The central
enzyme in
HC-toxin biosynthesis is a 570-kDa non-ribosomal
synthetase encoded by a 15.7-kb open reading frame. Other genes known to be required for
HC-toxin encode alpha and beta subunits of
fatty acid synthase, which are presumed to contribute to the synthesis of Aeo; a pathway-specific
transcription factor; an efflux carrier; a predicted
branched-chain amino acid aminotransferase; and an
alanine racemase.