The C-terminus of rat L-histidine decarboxylase specifically inhibits enzymic activity and disrupts pyridoxal phosphate-dependent interactions with L-histidine substrate analogues

Full-length rat HDC (L-histidine decarboxylase) translated in reticulocyte cell lysate reactions is inactive, whereas C-terminally truncated isoforms are capable of histamine biosynthesis. C-terminal processing of the similar to 74 kDa full-length protein occurs naturally in vivo, with the production of multiple truncated isoforms. The minimal C-terminal truncation required for the acquisition of catalytic competence has yet to be defined, however, and it remains unclear as to why truncation is needed. Here we show that similar to 74 kDa HDC monomers can form dinners, which is the conformation in which the enzyme is thought to be catalytically active. Nevertheless, the resulting dimer is unable to establish pyridoxal phosphate-dependent interactions with an L-histidine substrate analogue. Protein sequences localized to between amino acids 617 and 633 specifically mediate this inhibition. Removing this region or replacing the entire C-terminus with non-HDC protein sequences permitted interactions with the substrate analogue to be re-established. This corresponded exactly with the acquisition of catalytic competence, and the ability to decarboxylate natural L-histidine substrate. These studies suggested that the similar to 74 kDa full-length isoform, is deficient in substrate binding, and demonstrated that C-terminally truncated isoforms with molecular masses between similar to 70 kDa and similar to 58 kDa have gradually increasing specific activities. The physiological relevance of our results is discussed in the context of differential expression of HDC isoforms in vivo.