Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study DOI Creative Commons
Thirakorn Mokkawes, Sam P. de Visser

ChemistryEurope, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 7, 2024

Abstract Serotonin is a hormone that responsible for mood regultion in the brain; however, details on its biosynthetic mechanism remain controversial. Tryptophan hydroxylase catalyzes first step serotonin biosynthesis human body, where it regio‐ and stereoselectively hydroxylates free tryptophan (Trp) amino acid at C 5 ‐position. In this work, we present computational study ranging from molecular dynamics (MD) to quantum mechanics (QM) methods, focused of hydroxylase. An MD simulation an enzyme structure with substrate, co‐substrate dioxygen bound reveals tightly conformation substrate co‐substrate, while protein's three‐dimensional stays virtually intact during simulation. Subsequently, large active‐site cluster models containing more than 200 atoms were created, oxygen atom transfer reactions studied. The calculations predict co‐factor tetrahydrobiopterin binds covalently iron center react molecule form iron(IV)‐oxo species pterin‐4a‐carbinolamine stepwise manner small energy barriers (<5 kcal mol −1 ) along exergonic pathway. However, rate‐determining step, Trp activation through C−O transition state, followed by rapid proton relay produce 5‐hydroxy‐L‐Trp.

Language: Английский

Molecular dynamics, docking and quantum calculations reveal conformational changes influenced by CYP271A amino acid mutations related to cerebrotendinous xanthomatosis DOI Creative Commons
Yudibeth Sixto‐López, Humberto L. Mendoza‐Figueroa, Bruno Landeros‐Rivera

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 25, 2025

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid disorder caused by a deficiency in CYP27A1, the first enzyme bile acid biosynthesis pathway. CYP27A1 catalyzes 7α-hydroxylation of cholesterol, playing important role cholesterol homeostasis. CTX leads to progressive neurological dysfunction, including cognitive impairment, epilepsy, peripheral neuropathy, and movement disorders. Missense mutations disrupt its activity, particularly at heme binding region adrenodoxin-binding site. This study examined structural effects seven-point using molecular dynamic (MD) simulations. Both mutant wild-type (WT) proteins were modeled observe their behavior. Additionally, combining MD simulations, docking, quantum calculations was studied WT proteins. Results indicated that altered mode, preventing it from adopting correct position catalytic The substrate access channel mutants became wider, shallower, or closed. interaction between isopropyl group found be crucial for hydroxylation capacity as this only present cholesterol-WT complex.

Language: Английский

Citations

0
Insights into Active Site Cysteine Residues in Mycobacterium tuberculosis Enzymes: Potential Targets for Anti-Tuberculosis Intervention DOI Open Access
Abayomi S. Faponle, James W. Gauld, Sam P. de Visser

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3845 - 3845

Published: April 18, 2025

Cysteine, a semi-essential amino acid, is found in the active site of number vital enzymes bacterium Mycobacterium tuberculosis (Mtb) and particular those that relate to its survival, adaptability pathogenicity. Mtb causative agent tuberculosis, an infectious disease affects millions people globally. Common anti-tuberculosis targets are focused on immobilizing cysteine acid residue plays critical roles redox non-redox catalysis, modulation protein, enzyme activity, protein structure folding, metal coordination, posttranslational modifications newly synthesized proteins. This review examines five contain considered as key for drugs, namely alkyl hydroperoxide reductase (AhpC), dihydrolipoamide dehydrogenase (Lpd), aldehyde (ALDH), methionine aminopeptidase (MetAP) cytochromes P450. AhpC Lpd protect against oxidative nitrosative stress, whereas neutralizes peroxide/peroxynitrite substrates with two residues. ALDH detoxifies aldehydes, using nucleophilic form oxyanion thiohemiacetal intermediate, MtMetAP’s essential substrate recognition. The P450s metabolize various endogenous exogenous compounds. Targeting these residues could disrupt functions, presenting promising avenue developing anti-mycobacterial agents.

Language: Английский

Citations

0
Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study DOI Creative Commons
Thirakorn Mokkawes, Sam P. de Visser

ChemistryEurope, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 7, 2024

Abstract Serotonin is a hormone that responsible for mood regultion in the brain; however, details on its biosynthetic mechanism remain controversial. Tryptophan hydroxylase catalyzes first step serotonin biosynthesis human body, where it regio‐ and stereoselectively hydroxylates free tryptophan (Trp) amino acid at C 5 ‐position. In this work, we present computational study ranging from molecular dynamics (MD) to quantum mechanics (QM) methods, focused of hydroxylase. An MD simulation an enzyme structure with substrate, co‐substrate dioxygen bound reveals tightly conformation substrate co‐substrate, while protein's three‐dimensional stays virtually intact during simulation. Subsequently, large active‐site cluster models containing more than 200 atoms were created, oxygen atom transfer reactions studied. The calculations predict co‐factor tetrahydrobiopterin binds covalently iron center react molecule form iron(IV)‐oxo species pterin‐4a‐carbinolamine stepwise manner small energy barriers (<5 kcal mol −1 ) along exergonic pathway. However, rate‐determining step, Trp activation through C−O transition state, followed by rapid proton relay produce 5‐hydroxy‐L‐Trp.

Language: Английский

Citations

0