Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece.
PLoS One. 2010 Nov 1;5(11):e13781. doi: 10.1371/journal.pone.0013781.
The gene family of human kallikrein-related peptidases (KLKs) encodes proteins with diverse and pleiotropic functions in normal physiology as well as in disease states. Currently, the most widely known KLK is KLK3 or prostate-specific antigen (PSA) that has applications in clinical diagnosis and monitoring of prostate cancer. The KLK gene family encompasses the largest contiguous cluster of serine proteases in humans which is not interrupted by non-KLK genes. This exceptional and unique characteristic of KLKs makes them ideal for evolutionary studies aiming to infer the direction and timing of gene duplication events. Previous studies on the evolution of KLKs were restricted to mammals and the emergence of KLKs was suggested about 150 million years ago (mya). In order to elucidate the evolutionary history of KLKs, we performed comprehensive phylogenetic analyses of KLK homologous proteins in multiple genomes including those that have been completed recently. Interestingly, we were able to identify novel reptilian, avian and amphibian KLK members which allowed us to trace the emergence of KLKs 330 mya. We suggest that a series of duplication and mutation events gave rise to the KLK gene family. The prominent feature of the KLK family is that it consists of tandemly and uninterruptedly arrayed genes in all species under investigation. The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci. All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences. The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs.
人激肽释放酶相关肽酶（KLKs）基因家族编码具有多种功能的蛋白质，在正常生理状态以及疾病状态下都具有重要作用。目前，研究最为广泛的 KLK 是 KLK3 或前列腺特异性抗原（PSA），它在前列腺癌的临床诊断和监测中具有应用价值。KLK 基因家族包含了人类最大的连续的丝氨酸蛋白酶簇，其间没有非 KLK 基因的插入。KLKs 的这一独特特性使它们成为研究基因复制事件的方向和时间的理想选择，这些研究主要集中在进化方面。以前关于 KLKs 进化的研究仅限于哺乳动物，KLKs 的出现被认为发生在大约 1.5 亿年前（mya）。为了阐明 KLKs 的进化历史，我们对多个基因组中的 KLK 同源蛋白进行了全面的系统发育分析，包括最近完成的基因组。有趣的是，我们能够鉴定出新型的爬行动物、鸟类和两栖动物 KLK 成员，从而能够追溯到 3.3 亿年前 KLKs 的出现。我们认为，一系列的复制和突变事件导致了 KLK 基因家族的产生。KLK 家族的显著特征是，在所有被研究的物种中，它由串联且不间断排列的基因组成。在单个簇中的染色体共定位将 KLKs 与胰蛋白酶和其他胰蛋白酶样蛋白酶区分开来，后者分散在不同的遗传基因座中。KLKs 的所有特征在新型 KLK 蛋白序列中进一步被保守。对这个独特家族的研究将进一步有助于选择新的模式生物，用于涉及 KLKs 的蛋白水解途径的功能研究。
