Molecular and Evolution In Silico Studies Unlock the h4-HPPD C-Terminal Tail Gating Mechanism

The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It catalyzes the conversion of 4-hydroxyphenylpyruvate to a homogenisate in the presence of molecular oxygen and Fe(II) as a cofactor....

Full description

Saved in:
Bibliographic Details
Published in:Biomedicines 2024-05, Vol.12 (6), p.1196
Main Authors: Trezza, Alfonso, Birgauan, Ancuta, Geminiani, Michela, Visibelli, Anna, Santucci, Annalisa
Format: Article
Language:English
Subjects:
4-HPPD
4-Hydroxyphenylpyruvate dioxygenase
Amino acids
Bioinformatics
C-terminal tail
Catalysis
Conformation
Enzymes
Gating
Gram-positive bacteria
Hydrogen bonding
molecular dynamics simulations
molecular modeling
Molecular modelling
mutagenesis
Proteins
Simulation
Tyrosine
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It catalyzes the conversion of 4-hydroxyphenylpyruvate to a homogenisate in the presence of molecular oxygen and Fe(II) as a cofactor. This enzyme represents a key step in the biosynthesis of important compounds, and its activity deficiency leads to severe, rare autosomal recessive disorders, like tyrosinemia type III and hawkinsinuria, for which no cure is currently available. The 4-HPPD C-terminal tail plays a crucial role in the enzyme catalysis/gating mechanism, ensuring the integrity of the active site for catalysis through fine regulation of the C-terminal tail conformation. However, despite growing interest in the 4-HPPD catalytic mechanism and structure, the gating mechanism remains unclear. Furthermore, the absence of the whole 3D structure makes the bioinformatic approach the only possible study to define the enzyme structure/molecular mechanism. Here, wild-type 4-HPPD and its mutants were deeply dissected by applying a comprehensive bioinformatics/evolution study, and we showed for the first time the entire molecular mechanism and regulation of the enzyme gating process, proposing the full-length 3D structure of human 4-HPPD and two novel key residues involved in the 4-HPPD C-terminal tail conformational change.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines12061196