Carbonyl reductases from Daphnia are regulated by redox cycling compounds

Abstract

Oxidative stress is a major source of reactive carbonyl compounds that can damage cellular macromolecules, leading to so-called carbonyl stress. Aside from endogenously formed carbonyls, including highly reactive short-chain aldehydes and diketones, air pollutants derived from diesel exhaust like 9,10-phenanthrenequinone (PQ) can amplify oxidative stress by redox cycling, causing tissue damage. Carbonyl reductases (CRs), which are inducible in response to ROS, represent a fundamental enzymatic defense mechanism against oxidative stress. While commonly two carbonyl reductases (CBR1 and CBR3) are found in mammalian genomes, invertebrate model organisms like Drosophila melanogaster express no CR but a functional homolog to human CBR1, termed sniffer. The microcrustacean Daphnia is an ideal model organism to investigate the function of CRs because of its unique equipment with even four copies of the CR gene (CR1, CR2, CR3, CR4) in addition to one sniffer gene. Cloning and catalytic characterization of two carbonyl reductases CR1 and CR3 from D. magna and D. pulex arenata revealed that both proteins reductively metabolize aromatic dicarbonyls (e.g., menadione, PQ) and aliphatic α-diketones (e.g., 2,3-hexanedione), while sugar-derived aldehydes (methylglyoxal, glyoxal) and lipid peroxidation products such as acrolein and butanal were poor substrates, indicating no physiological function in the metabolism of short-chain aldehydes. Treatment of D. magna with redox cyclers like menadione and the pesticide paraquat led to an upregulation of CR1 and CR3 mRNA, suggesting a role in oxidative stress defense. Further studies are needed to investigate their potential to serve as novel biomarkers for oxidative stress in Daphnia.

The explosive trinitrotoluene (TNT) induces gene expression of carbonyl reductase in the blue mussel (Mytilus spp.): a new promising biomarker for sea dumped war relicts?

“…In the present investigation we, therefore, focused on the metabolic antioxidant defence system on a molecular level and concentrated on the induction of the carbonyl reductase gene which is known to respond to oxidative stress and reactive oxygen species (ROS) (Ebert et al 2018 ). The existence of ROS is an integral part of human and animal life.…”

“…On the other hand, xenobiotics that constantly enter living individuals can either directly be metabolized to ROS or they cause damages to cell components like DNA, proteins and other essential structures, which may contribute to the formation of ROS as well (Lushchak 2011 ). Fortunately, cellular organisms are able to protect themselves with the help of several non-enzymatic and enzymatic mechanisms (Ebert et al 2018 ).…”

“…Here, carbonyl reducing enzymes play an important role in the defence against cellular damages caused by oxidative stress and ROS, thereby providing neuroprotection against reactive carbonyl compounds (Botella et al 2004 ; Maser 2006 ; Ellis 2007 ). For example, human carbonyl reductase 1 (CBR1; SDR21C1) was first identified in the human brain (Wermuth 1981 ) and later shown to play a role in the protection against lipid peroxidation derived reactive aldehydes (Doorn et al 2004 ; Maser 2006 ), thereby constituting a defence mechanism against oxidative stress in general and carbonyl stress in more detail (Ebert et al 2018 ). Later, human carbonyl reductase 3 (CBR3; SDR21C2) was characterized (Watanabe et al 1998 ).…”

“…Interestingly, the model organism Drosophila melanogaster has no carbonyl reductase gene but an unrelated gene called sniffer (Botella et al 2004 ) which was shown to provide protection against carbonyl stress in Drosophila (Martin et al 2011 ). Bioinformatics analyses on another model organism resulted in the identification of the sniffer gene and four additional genes coding for four individual carbonyl reductases, CR1 – CR4, in the Daphnia genome (Ebert et al 2018 ). We cloned all four Daphnia carbonyl reductases from D. magna and D. pulex , respectively, and showed their high affinity toward aromatic dicarbonyls including redox cyclers such as phenanthrene quinone, implying their physiological role in the detoxification of quinones (Ebert et al 2018 ).…”

Flubendazole carbonyl reduction in drug-susceptible and drug-resistant strains of the parasitic nematode Haemonchus contortus: changes during the life cycle and possible inhibition

“…Menadione has also been shown to be a substrate of carbonyl reductase in Daphnia spp. [ 28 ]. The flavonoids luteolin and naringenin inhibit human CBR1, with luteolin acting as a potent CBR1 inhibitor [ 29 , 30 ].…”