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  • The CYP A structure manifest larger active site and

    2020-07-30

    The CYP3A4 structure manifest larger active site and a closely existing large solvent channel to facilitate oxidation of larger or multiple substrate. This solvent channel is formed by interaction among tyrosine (Y-53), aspartic FIPI (D-61), aspartic acid (D-76), arginine (R-106), arginine FIPI (R-372) and glutamic acid (E-374) [31]. These characteristic residues except the glutamic acid (E-374) that is replaced by less hydrophilic tyrosine (Y-374), are present at the same position in CYP3A163 suggesting the capability to oxidise larger or multiple substrates with likely differences towards substrate specificity. The signature haem binding motif of ten amino acids for all CYPs FXXGXXXCXG (FGAGPRNCLG, 442-451) with a basic amino acid (R) at the sixth position important for interaction with redox partners and the cysteine at eighth position is absolutely conserved in this decapeptide [34]. C-449 coordinates to the haem iron as a fifth ligand, necessary for the functional properties of CYPs to oxidize inactivated C-C or C–H bonds and electron transfer interactions [38], [39]. Beyond this conserved motif is another conserved tetrapeptide LQNF (467-470) [27]. The sequence identity of CYP3A163 with CYP3A sequences from other species is maximum in reptiles ranging (75-91)%, gradually decreasing from birds (63-71)% to mammals 62% to downwards based on evolutionary distances. The high level of homology with CYP3A77 in Alligator mississippiensis suggest that CYP3A163 shares similar structural, functional and regulatory profiles such as strong induction of CYP3A77 in Alligator mississippiensis by dexamethasone and toxaphene [40]. The results suggest comparable catalytic profile of CYP3A163 with human CYP3A4 and require further validation by molecular docking analysis, catalytic and mutagenic studies. This study opens more avenues to investigate evolution of this incredible species in relation to CYP superfamily, to establish the structure-activity relationship and mechanism of action, to explore functional breadth, to find therapeutic, toxicological effects of xenobiotics and to improve the health and survival rate contributing in the conservation management practices.
    Declaration of interest
    Introduction The glucocorticoid receptor (GR) mediates the hepatic regulation and expression of cytochrome P450 genes which are engaged in the metabolism of drugs and endogenous compounds. Of the cytochrome CYP isoforms, CYP3A is one of the most important cytochrome P450 subfamilies responsible for the metabolism of clinically important drugs and endogenous steroids [16]. Interestingly, conditional inactivation of the glucocorticoid receptor gene in cells expressing dopamine-β-hydroxylase, an enzyme necessary for the synthesis of noradrenaline and adrenaline in the central and the peripheral nervous systems, showed that glucocorticoid-dependent signaling was required for the survival of chromaffin cells [12]. The abovedescribed action also seems to be important for the metabolic function of the liver, since chromaffin cells can be seen in the liver to form clusters in portal areas, or are spotted as single cells in the walls of liver sinusoids and in the region below the connective capsule [10]. Regulation of the expression of mouse CYP3A genes is under multi-hormonal control, in which the growth hormone (GH) and sex hormones play a pivotal role [14]. Furthermore, the noradrenergic system is engaged in the regulation of CYP3A activity. Previous studies have shown that intraperitoneal administration of DSP-4 markedly decreases the activity of CYP3A, but not its protein level, in the liver of male rats [7]. But recent studies have indicated that intracerebroventricular administration of low doses of DSP-4 decreases both the activity and the protein of CYP3A, in the liver of male rats [13]. However, the fact is that DSP-4 which is a toxin specific to noradrenergic neurons in the central and the peripheral nervous system can also very easy pass the brain-blood barrier (to the brain and out of the brain) independently of the routes of administration of DSP-4 [3, 4]. Therefore, the present preliminary study investigated the effect of glucocorticoid receptor selective ablation in the noradrenergic system on the activity of the CYP3A isoform in mouse liver.