Autocatalytic Peptide Cyclization during Chain Folding of Histidine Ammonia-Lyase

• Published in: Structure (London) Vol. 10; no. 1; pp. 61 - 67
• Main Authors: Baedeker, Mathias, Schulz, Georg E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2002
• Subjects: 4-methylidene-imidazole-5-one (MIO); Binding Sites; Crystallography, X-Ray; Cyclization; Dehydration; green fluorescent protein; Histidine Ammonia-Lyase - chemistry; Histidine Ammonia-Lyase - genetics; Histidine Ammonia-Lyase - metabolism; Models, Molecular; Molecular Structure; Peptides - chemistry; Peptides - metabolism; peptidic electrophile; posttranslational modification; Protein Folding; Protein Structure, Tertiary; Pseudomonas putida - enzymology; X-ray structure analysis; 4-methylidene-imidazole-5-one (MIO); peptidic electrophile; X-ray structure analysis; Dehydration; green fluorescent protein; posttranslational modification
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(01)00692-X

Histidine ammonia-lyase requires a 4-methylidene-imidazole-5-one group (MIO) that is produced autocatalytically by a cyclization and dehydration step in a 3-residue loop of the polypeptide. The crystal structures of three mutants have been established. Two mutants were inactive and failed to form MIO, but remained unchanged elsewhere. The third mutant showed very low activity and formed MIO, although it differed from an MIO-less mutant only by an additional 329-C β atom. This atom forms one constraint during MIO formation, the other being the strongly connected Asp145. An exploration of the conformational space of the MIO-forming loop showed that the cyclization is probably enforced by a mechanic compression in a late stage of chain folding and is catalyzed by a well-connected internal water molecule. The cyclization of the respective 3-residue loop of green fluorescent protein is likely to occur in a similar reaction.