Histidine ammonia-lyase

 

This enzyme catalyses the first step in the degradation of histidine and the product, urocanic acid, is further metabolized to glutamate, the first step of the subpathway that synthesizes N-formimidoyl-L-glutamate from L-histidine. It is a member of the aromatic amino acid lyase family.

The enzyme contains the cofactor 3,5-dihydro-5-methylidene-4H-imidazol-4-one (MIO), which is common to this family [PMID:17185228]. This unique cofactor is formed autocatalytically by cyclization and dehydration of the three amino-acid residues alanine, serine and glycine [PMID:10220322].

histidine ammonia-lyases (HAL) triggers the abstraction of the nonacidic beta protons of histidine, leaving the much more acidic ammonium hydrogen atoms untouched.

 

Reference Protein and Structure

Sequence
P21310 UniProt (4.3.1.3) IPR005921 (Sequence Homologues) (PDB Homologues)
Biological species
Pseudomonas putida (Bacteria) Uniprot
PDB
1b8f - Histidine ammonia-lyase (HAL) from Pseudomonas putida (2.1 Å) PDBe PDBsum 1b8f
Catalytic CATH Domains
1.10.275.10 CATHdb 1.20.200.10 CATHdb (see all for 1b8f)
Cofactors
2-[(1s)-1-aminoethyl]-1-carboxymethyl-5-hydroxy-4-methylimidazole (1), Zinc(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:4.3.1.3)

L-histidine zwitterion
CHEBI:57595ChEBI
→
trans-urocanate
CHEBI:17771ChEBI
+
ammonium
CHEBI:28938ChEBI
Alternative enzyme names: Histidase, Histidinase, Histidine alpha-deaminase, L-histidine ammonia-lyase,

Enzyme Mechanism

Introduction

Tyr280 deprotonates the zwitterioninc amine as it enters the active site. The histidine substrate then attacks the MIO in a nucleophilic addition. Glu414 abstracts the beta proton and concurrently eliminates the ammonia. The urocanate product leaves first, followed by ammonia, that abstracts the proton from Tyr280 as it leaves. It is thought that zinc also plays a critical role in the reaction by coordinating the substrate.

Catalytic Residues Roles

UniProt PDB* (1b8f)
Phe330 Phe329(327)A Helps stabilise the MIO cofactor through pi-pi stacking. electrostatic stabiliser
Asn196 Asn195(193)A Helps make the ammonia a better leaving group. activator
Glu415 Glu414(412)A Acts as a general acid/base during the course of the reaction. proton shuttle (general acid/base)
His84 His83A Helps stabilise the intermediates formed. electrostatic stabiliser
Tyr281 Tyr280(278)A(AA) Plays a critical role in the activation of the amino acid by abstracting a proton from the zwitterionic amine. It is later returned to its anionic state by the ammonia product. proton shuttle (general acid/base)
Tyr54, Arg284 Tyr53A, Arg283(281)A(AA) Acts to bind and stabilise the carboxylic acid group of the histidine product. electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Poppe L et al. (2005), Angew Chem Int Ed Engl, 44, 3668-3688. Friedel-Crafts-Type Mechanism for the Enzymatic Elimination of Ammonia from Histidine and Phenylalanine. DOI:10.1002/anie.200461377. PMID:15906398.
  2. Sánchez-Murcia PA et al. (2016), Biochemistry, 55, 5854-5864. Stepwise Simulation of 3,5-Dihydro-5-methylidene-4H-imidazol-4-one (MIO) Biogenesis in Histidine Ammonia-lyase. DOI:10.1021/acs.biochem.6b00744. PMID:27682658.
  3. Seff AL et al. (2011), J Mol Model, 17, 1551-1563. Computational investigation of the histidine ammonia-lyase reaction: a modified loop conformation and the role of the zinc(II) ion. DOI:10.1007/s00894-010-0849-7. PMID:20922445.
  4. Baedeker M et al. (2002), Eur J Biochem, 269, 1790-1797. Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism. DOI:10.1046/j.1432-1327.2002.02827.x.
  5. Röther D et al. (2001), Eur J Biochem, 268, 6011-6019. Characterization of the active site of histidine ammonia-lyase from Pseudomonas putida. DOI:10.1046/j.0014-2956.2001.02298.x.
  6. Schwede TF et al. (1999), Biochemistry, 38, 5355-5361. Crystal Structure of Histidine Ammonia-Lyase Revealing a Novel Polypeptide Modification as the Catalytic Electrophile†,‡. DOI:10.1021/bi982929q. PMID:10220322.

Step 1.

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Catalytic Residues Roles

Residue Roles
Glu414(412)A proton shuttle (general acid/base)
Asn195(193)A activator
Tyr53A electrostatic stabiliser
Arg283(281)A(AA) electrostatic stabiliser
His83A electrostatic stabiliser
Phe329(327)A electrostatic stabiliser
Tyr280(278)A(AA) proton shuttle (general acid/base)

Chemical Components

Step 1.

Contributors

Alex Gutteridge, Craig Porter, Gemma L. Holliday