Abstract
Kallikreins are secreted serine proteases with important roles in human physiology. Human plasma kallikrein, encoded by the KLKB1 gene on locus 4q34-35, functions in the blood coagulation pathway, and in regulating blood pressure. The human tissue kallikrein and kallikrein-related peptidases (KLKs) have diverse expression patterns and physiological roles, including cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis. Prostate-specific antigen (PSA), the product of the KLK3 gene, is the most widely used biomarker in clinical practice today. A total of 15 KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4), which makes them ideal for evolutionary analysis of gene duplication events. Previous studies on the evolution of KLKs have traced mammalian homologs as well as a probable early origin of the family in aves, amphibia and reptilia. The aim of this study was to address the evolutionary and functional relationships between tissue KLKs and plasma kallikrein, and to examine the evolution of alternative splicing isoforms. Sequences of plasma and tissue kallikreins and their alternative transcripts were collected from the NCBI and Ensembl databases, and comprehensive phylogenetic analysis was performed by Bayesian as well as maximum likelihood methods. Plasma and tissue kallikreins exhibit high sequence similarity in the trypsin domain (>50%). Phylogenetic analysis indicates an early divergence of KLKB1, which groups closely with plasminogen, chymotrypsin, and complement factor D (CFD), in a monophyletic group distinct from trypsin and the tissue KLKs. Reconstruction of the earliest events leading to the diversification of the tissue KLKs is not well resolved, indicating rapid expansion in mammals. Alternative transcripts of each KLK gene show species-specific divergence, while examination of sequence conservation indicates that many annotated human KLK isoforms are missing the catalytic triad that is crucial for protease activity.
Highlights
Peptidases or proteases, are enzymes that break down a polypeptide or protein by cleaving peptide bonds
The human tissue kallikrein-related peptidases (KLKs) protein sequences have an average length of approximately 260 amino acids, and contain a trypsin-like protease domain that spans almost the full length of the protein (Figure 1)
The only exception is that plasma kallikrein contains one extra intron, i.e. the corresponding third exon from tissue kallikreins is split into two exons (Figure 1)
Summary
Peptidases or proteases, are enzymes that break down a polypeptide or protein by cleaving peptide bonds Proteolytic enzymes, their substrates and inhibitors, are of great interest in biology, medicine, and biotechnology. Apart from their role in the breakdown of misfolded or unnecessary proteins, proteases affect the localization and activity of many gene products, and are of great importance to signaling pathways. Their function affects cell proliferation and differentiation, immunity, homeostasis, inflammation, blood coagulation, autophagy, necrosis, and apoptosis [1]. Plasma and tissue kallikreins are members of the serine protease family S1 (S1A subfamily of the PA(S) serine peptidase clan [4,5])
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