Enzymology in histamine biogenesis

Abstract

Histamine is a multifunctional biogenic amine with relevant roles in intercellular communication, inflammatory processes and many emergent pathologies. Histamine biosynthesis depends on the single decarboxylation of the amino acid histidine. In Gram-negative bacteria and animals, this reaction is carried out by a PLP-dependent histidine decarboxylase activity (HDC, EC 4.1.1.22), an enzyme that has been rather difficult to experimentally characterize. Interest in the mammalian HDC has increased due to recent findings on physiological consequences observed in HDC knockout animals. During the last few years, important advances have been made in the study of the structure/function relationship that explains its catalytic behaviour, mainly through a combination of both biophysical and biocomputational approaches. This chapter provides a comprehensive review of the current knowledge on this topic and how this knowledge could be extracted, which could give insights to characterize other unstable and minor proteins with physiopathological relevance. A model for the structure of the enzyme allowed us to understand its topology and to locate the catalytic environment, which was validated by direct-mutagenesis. Hybrid quantum mechanics and molecular mechanics simulations made it possible to understand the decarboxylation reaction at atomic level, as well as the conformational changes of the enzyme caused by the substrate binding. At this point, the search for and design of new and more selective modulators of the activity are possible. We also point out some important outstanding problems: (i) the exact role of the carboxy-terminal portion of the primary translation product; (ii) the putative binding proteins that can explain several intracellular features deduced for this enzyme; and (iii) the need for a deeper comparison to the unsolved PLP-dependent bacterial counterpart and other homologous enzymes. © Springer Science+Business Media B.V. 2010.