Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Histamine is a crucial mediator in numerous physiological processes.
• L-histidine decarboxylase (HDC) catalyzes the synthesis of histamine from histidine.
• Understanding HDC's structure and function is vital for comprehending histamine regulation.

Purpose of the Study:

• To elucidate the structural basis of human HDC (hHDC) activity.
• To investigate the role of specific residues in substrate recognition.
• To provide molecular insights into pyridoxal-5'-phosphate-dependent decarboxylases.

Main Methods:

• X-ray crystallography was used to determine the structure of hHDC complexed with histidine methyl ester.
• Structural comparison between hHDC and aromatic L-amino acid decarboxylase.
• Site-directed mutagenesis (S354G) to analyze substrate specificity.

Main Results:

• The crystal structure revealed detailed features of the pyridoxal-5'-phosphate adduct at the hHDC active site.
• Serine-354 was identified as a critical residue for substrate specificity.
• The S354G mutation altered the substrate-binding pocket, decreasing histidine affinity but enabling L-DOPA binding and activity.

Conclusions:

• The study provides a detailed structural understanding of hHDC inhibition.
• Serine-354 plays a pivotal role in distinguishing between histidine and other amino acid substrates.
• These findings illuminate the molecular mechanisms underlying substrate specificity in group II pyridoxal-5'-phosphate-dependent decarboxylases.