Human Secretary Phospholipase A2 Mutations and Their Clinical Implications

Abstract

Phospholipases A2 (PLA₂s) belong to a superfamily of enzymes responsible for hydrolysis of the sn-2 fatty acids of membrane phospholipids to release arachidonic acid. PLA₂s 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 (sPLA₂) 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 sPLA₂ 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 sPLA₂ 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 sPLA₂ 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 sPLA₂ 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.

Keywords: clinical implications; mutations; sPLA2; secretary phospholipase A2; structure–function relationship.

Figure 1

Diagrammatic representation showing the chemical bonds on the phospholipid substrate that are cleaved by the enzymes in the phospholipase family.

Figure 2

Ribbon diagram showing the overall structure of human group III PLA₂, a prototype human sPLA₂. Structure comprises of three helices, indicated as H1, H2, and H3; two β-wings, indicated as β1 and β2; calcium binding loop (pink) with the calcium ion (sphere in magenta); active site with residues histidine 34 and aspartic acid 63; C-terminal extension; and stabilized by five disulfide bonds (yellow). The structure was done using homology modeling on human group III PLA₂ sequence (Q9NZ20), and viewed on Pymol.