Atomic structure of GTP cyclohydrolase I

Area of Science:

• Biochemistry and Structural Biology
• Enzyme kinetics and mechanism
• Protein structure-function relationships

Background:

• Tetrahydrobiopterin is a crucial cofactor for neurotransmitter synthesis and immune regulation.
• Its biosynthesis begins with GTP, catalyzed by GTP cyclohydrolase I (GTP-CH-I).
• GTP-CH-I initiates the complex conversion of a purine into the pterin ring system.

Purpose of the Study:

• To determine the three-dimensional structure of Escherichia coli GTP cyclohydrolase I.
• To elucidate the quaternary structure and active site of GTP-CH-I.
• To compare the structural features of GTP-CH-I with other enzymes in the tetrahydrobiopterin biosynthesis pathway.

Main Methods:

• X-ray crystallography was employed to solve the crystal structure.
• Single isomorphous replacement and molecular averaging techniques were utilized.
• The structure was resolved at a resolution of 3.0 Å.

Main Results:

• The crystal structure of E. coli GTP-CH-I was determined, revealing a homodecameric complex with D5 symmetry.
• The enzyme forms a torus-like structure composed of pentameric subunits, each featuring a unique 20-stranded antiparallel beta-barrel.
• The C-terminal domain of GTP-CH-I shares topological similarity with 6-pyruvoyl tetrahydropterin synthase.

Conclusions:

• The active site of GTP-CH-I is at a three-subunit interface, featuring a novel GTP-binding site.
• The catalytic mechanism likely involves histidines and potentially cysteine.
• Despite sequence differences, GTP-CH-I and 6-pyruvoyl tetrahydropterin synthase share conserved structural features for pterin biosynthesis.