The V279F polymorphism might change protein character and immunogenicity in Lp-PLA2 protein

Widodo, Widodo; Ramadhani, Anggia Noor; NofitaSari, Anissa; Puspitarini, Sapti; Priyandoko, Didik; Rohman, Mohammad Saifur; Lukitasari, Mifetika

doi:10.1016/j.ejmhg.2017.08.001

Cited by 3 publications

(1 citation statement)

References 29 publications

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“…This study also lays the platform to understand the functional and clinical outcomes in pPAF-AH enzymes and provides an opportunity to develop therapeutic interventions to overcome it. [44,47,48] • Tilt in the axis of H5 to avoid stearic clashes with the hydrophobic residues on the β-sheets adjacent to it…”

Section: Resultsmentioning

confidence: 99%

Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme

Khan

Hariprasad

2020

JIR

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Purpose To investigate the structural features of wild and mutant forms of the pPAF-AH enzyme that are responsible for coronary artery disease. Methods Mutant variants of human pPAF-AH having either V279F, Q281R, or both were modelled and evaluated for stereo chemical and structural correctness. The 3D coordinates of substrate PAF were retrieved from the PubChem database was solvated and minimized on Discovery Studio, and docked to the wild and mutant enzyme models. The top docked pose complex was refined by MD simulation. Results pPAF-AH model comprises of 420 amino acids in a α/β-hydrolase fold that contains a substrate-binding hydrophobic channel with an active site pocket having a catalytic triad of Ser273, Asp296 and His351. Mutations at positions 279 and 281 are opposite one another on the middle of 12 residues long H5 helix that forms the hydrophobic core of the enzyme. V279F causes a tilt on the axis of the mutation bearing helix to avoid steric clashes with the hydrophobic residues on the β-sheets adjacent to it, inducing subtle conformational changes on the H5-β8 loop, β8 sheet, and the loop bearing Asp296. A cascade of conformational changes induces a change in the orientation of His351 resulting in loss of hydrogen bonded interaction with catalytic Ser273. Q281R causes a shortening of H5 and β8, which induces conformational changes of the loops bearing Ser273 and Asp296, respectively. Simultaneous conformational changes of secondary structural elements result in the flipping of His351 causing a break in the catalytic triad. Also, there is a compromise in the substrate-binding area and volume in the mutants resulting in loss of binding to its substrate. Conclusion Mutant enzymes show changes at the site of the mutation, secondary motif conformations and global structural conformations that adversely affect the active site, decrease substrate channel volume and decrease stability, thereby affecting enzymatic function.

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Section: Resultsmentioning

confidence: 99%

Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme

Khan

Hariprasad

2020

JIR

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Structural insights and functional aspects of phospholipase A2 and phospholipase D in cancer therapy

Mekala,

Chamarthy,

Ramalingam

et al. 2023

Phospholipases in Physiology and Pathology

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Human Secretary Phospholipase A2 Mutations and Their Clinical Implications

Khan

Hariprasad

2020

JIR

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Phospholipases A2 (PLA 2 s) belong to a superfamily of enzymes responsible for hydrolysis of the sn-2 fatty acids of membrane phospholipids to release arachidonic acid. PLA 2 s are the rate limiting enzyme for the downstream synthesis of prostaglandins and leukotrienes that are the main mediators of inflammation. The extracellular forms of this enzyme are also called the secretary phospholipase A2 (sPLA 2) and are distributed extensively in most of the tissues in the human body. Their integral role in inflammatory pathways has been the primary reason for the extensive research on this molecule. The catalytic mechanism of sPLA 2 is initiated by a histidine/aspartic acid/calcium complex within the active site. Though they are known to have certain housekeeping functions, certain mutations of sPLA 2 are known to be implicated in causation of certain pathologies leading to diseases such as atherosclerosis, cardiovascular diseases, benign fleck retina, neurodegeneration, and asthma. We present an overview of human sPLA 2 and a comprehensive compilation of the mutations that result in various disease phenotypes. The study not only helps to have a holistic understanding of human sPLA 2 mutations and their clinical implications, but is also a useful platform to initiate research pertaining to structure-function relationship of the mutations to develop effective therapies for management of these diseases.

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The V279F polymorphism might change protein character and immunogenicity in Lp-PLA2 protein

Cited by 3 publications

References 29 publications

<p>Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme</p>

<p>Structural Modeling of Wild and Mutant Forms of Human Plasma Platelet Activating Factor-Acetyl Hydrolase Enzyme</p>

Structural insights and functional aspects of phospholipase A2 and phospholipase D in cancer therapy

<p>Human Secretary Phospholipase A2 Mutations and Their Clinical Implications</p>

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