Computational insights into dynamics and conformational stability of N-acetylmannosamine kinase mutations.

Autor: Abdel-Naim AB; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia., Kumar P; School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India., Bazuhair MA; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia.; Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia., Rizg WY; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia.; Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Niyazi HA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Alkuwaity K; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.; Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia., Niyazi HA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Alharthy SA; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.; Toxicology and Forensic Sciences Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia., Harakeh S; King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.; Yousef Abdul Latif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia., Haque S; Research and Scientific Studies Unit, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia.; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon.; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates., Prakash A; Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurgaon, India., Kumar V; Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, India.
Jazyk: angličtina
Zdroj: Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2024 Mar 19, pp. 1-11. Date of Electronic Publication: 2024 Mar 19.
DOI: 10.1080/07391102.2024.2323702
Abstrakt: The activity of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) is essential for the biosynthesis of sialic acid, which is involved in cellular processes in health and diseases. GNE contains an N-terminal epimerase domain and a C-terminal kinase domain (N-acetylmannosamine kinase, MNK). Mutations of the GNE protein led to hypoactivity of the enzyme and cause sialurea or autosomal recessive inclusion body myopathy/Nonaka myopathy. Here, we used all-atom molecular dynamics (MD) simulations to comprehend the folding, dynamics and conformational stability of MNK variants, including the wild type (WT) and three mutants (H677R, V696M and H677R/V696M). The deleterious and destabilizing nature of MNK mutants were predicted using different prediction tools. Results predicted that mutations modulate the stability, flexibility and function of MNK. The effect of mutations on the conformational stability and dynamics of MNK was next studied through the free-energy landscape (FEL), hydrogen-bonds and secondary structure changes. The FEL results show that the mutations interfere with various conformational transitions in both WT and mutants, exposing the structural underpinnings of protein destabilization and unfolding brought on by mutation. We discover that, when compared to the other two mutations, V696M and H677R/V696M, H677R has the most harmful effects. These findings have a strong correlation with published experimental studies that demonstrate how these mutations disrupt MNK activity. Hence, this computational study describes the structural details to unravel the mutant effects at the atomistic resolution and has implications for understanding the GNE's physiological and pathological role.Communicated by Ramaswamy H. Sarma.
Databáze: MEDLINE
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