Insights into the substrate specificity, structure, and dynamics of plant histidinol-phosphate aminotransferase (HISN6)

Plant Physiol Biochem. 2023 Mar:196:759-773. doi: 10.1016/j.plaphy.2023.02.017. Epub 2023 Feb 10.


Histidinol-phosphate aminotransferase is the sixth protein (hence HISN6) in the histidine biosynthetic pathway in plants. HISN6 is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of imidazole acetol phosphate into L-histidinol phosphate (HOLP). Here, we show that plant HISN6 enzymes are closely related to the orthologs from Chloroflexota. The studied example, HISN6 from Medicago truncatula (MtHISN6), exhibits a surprisingly high affinity for HOLP, which is much higher than reported for bacterial homologs. Moreover, unlike the latter, MtHISN6 does not transaminate phenylalanine. High-resolution crystal structures of MtHISN6 in the open and closed states, as well as the complex with HOLP and the apo structure without PLP, bring new insights into the enzyme dynamics, pointing at a particular role of a string-like fragment that oscillates near the active site and participates in the HOLP binding. When MtHISN6 is compared to bacterial orthologs with known structures, significant differences arise in or near the string region. The high affinity of MtHISN6 appears linked to the particularly tight active site cavity. Finally, a virtual screening against a library of over 1.3 mln compounds revealed three sites in the MtHISN6 structure with the potential to bind small molecules. Such compounds could be developed into herbicides inhibiting plant HISN6 enzymes absent in animals, which makes them a potential target for weed control agents.

Keywords: Conformational change; Enzyme features; Histidinol-phosphate aminotransferase; Inhibition.

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Phosphates
  • Pyridoxal Phosphate*
  • Substrate Specificity
  • Transaminases* / chemistry
  • Transaminases* / metabolism


  • histidinol-phosphate aminotransferase
  • Transaminases
  • Pyridoxal Phosphate
  • Phosphates