Comparative genomics of duplicate γ‐glutamyl transferase genes in teleosts: medaka (Oryzias latipes), stickleback (Gasterosteus aculeatus), green spotted pufferfish (Tetraodon nigroviridis), fugu (Takifugu rubripes), and zebrafish (Danio rerio)

Abstract

The availability of multiple teleost (bony fish) genomes is providing unprecedented opportunities to understand the diversity and function of gene duplication events using comparative genomics. Here we examine multiple paralogous genes of γ-glutamyl transferase (GGT) in several distantly related teleost species including medaka, stickleback, green spotted pufferfish, fugu and zebrafish. Through mining genome databases, we have identified multiple GGT orthologs. Duplicate (paralogous) GGT sequences for GGT1 (GGT1 a and b), GGTL1 (GGTL1 a and b) and GGTL3 (GGTL3 a and b) were identified for each species. Phylogenetic analysis suggests that GGTs are ancient proteins conserved across most metazoan phyla and those paralogous GGTs in teleosts likely arose from the serial 3R genome duplication events. A third GGTL1 gene (GGTL1c) was found in green spotted pufferfish; however this gene is not present in medaka, stickleback or fugu. Similarly, one or both paralogs of GGTL3 appear to have been lost in green spotted pufferfish, fugu and zebrafish. Syntenic relationships were highly maintained between duplicated teleost chromosomes, among teleosts and across ray-finned (Actinopterygii) and lobe-finned (Sarcopterygii) species. To assess subfunction partitioning, six medaka GGT genes were cloned and assessed for developmental and tissue specific expression. Based upon these data, we propose a modification of the “duplication-degeneration-complementation” (DDC) model of subfunction partitioning where quantitative differences rather than absolute differences in gene expression are observed between gene paralogs. Our results demonstrate that multiple GGT genes have been retained within teleost genomes. Questions remain however regarding the functional roles of multiple GGTs in these species.

Immunolabeling of gamma-glutamyl transferase 5 in normal human tissues reveals that expression and localization differ from gamma-glutamyl transferase 1

“…Information on the expression of GGT5 in other vertebrates is derived primarily from mRNA studies in mice, rats and fish (Carter et al 1998; Potdar et al 1997; Law et al 2012). The most striking difference in GGT5 expression between mouse and human tissues was that in the mouse, macrophages lacked GGT5 expression, while in humans GGT5-positive macrophages were observed in many tissues (Carter et al 1998).…”

“…GGT1 is present in bacteria and throughout the plant and animal kingdoms while GGT5 is present only in vertebrates (Law et al 2012; Okada et al 2006; Bello and Epstein 2013). Phylogenetic analyses indicate that GGT5 arose from a duplication of the GGT1 gene in the vertebrate lineage after divergence from Branchiostoma but before the divergence of amphibians and teleost fish (Law et al 2012).…”

“…GGT1 is present in bacteria and throughout the plant and animal kingdoms while GGT5 is present only in vertebrates (Law et al 2012; Okada et al 2006; Bello and Epstein 2013). Phylogenetic analyses indicate that GGT5 arose from a duplication of the GGT1 gene in the vertebrate lineage after divergence from Branchiostoma but before the divergence of amphibians and teleost fish (Law et al 2012). We have expressed GGT5 and conducted kinetic analysis which has shown that human GGT5 (hGGT5) cleaves glutathione, LTC 4 and other glutathione conjugates but at a much slower rate than human GGT1 (hGGT1), with second order rate kinetics approximately 30-fold lower for hGGT5 compared to hGGT1 (Wickham et al 2011).…”

Rapid conversion and reversible conjugation of glutathione detoxification of microcystins in bighead carp (Aristichthys nobilis)

“…First, a number of carriers, such as members of the oatp/OATP superfamily, help to transport MC-RR-GSH to the kidney and/or help to transport MC-RR-Cys produced by other organs, such as the liver, into the kidney (Fischer et al, 2005;Hagenbuch and Meier, 2003;Lohr et al, 1998;Meier et al, 1997;Meier and Stieger, 2002). Additionally, the MC-RR-GSH arriving in the kidney was rapidly and effectively converted to MC-RR-Cys, as high gamma-glutamyltranspeptidase (GGT) and cysteinylglycine dipeptidase activities, which catalyze this conversion process, were found in the kidneys of mammals and fish (Elfarra and Anders, 1984;Hughey et al, 1978;Kera et al, 1999;Law et al, 2012). Previous studies observed significant induction of GGT genes in medaka larvae within 15 min after treatment with tert-butyl hydroquinone (tBHQ) in the rearing solution (Law et al, 2012).…”

“…Additionally, the MC-RR-GSH arriving in the kidney was rapidly and effectively converted to MC-RR-Cys, as high gamma-glutamyltranspeptidase (GGT) and cysteinylglycine dipeptidase activities, which catalyze this conversion process, were found in the kidneys of mammals and fish (Elfarra and Anders, 1984;Hughey et al, 1978;Kera et al, 1999;Law et al, 2012). Previous studies observed significant induction of GGT genes in medaka larvae within 15 min after treatment with tert-butyl hydroquinone (tBHQ) in the rearing solution (Law et al, 2012). Based on these related research data together with the present results, we infer that the renal metabolism may play a major role in the processing of MC-RR-GSH into MC-RR-Cys in fish like bighead carp, as well as in the accumulation of MC-RR-Cys in the kidney for excretion.…”