D-Amino acid oxidase activation

Hamase, K., Inoue, T., Morikawa, A., Konno, R., Zaitsu, K. (2001). Determination of free d-proline and D-leucine in the brains of mutant mice lacking D-amino acid oxidase activity. Anal. Biochem. 298, 253-258. 

Kochakian was the first to demonstrate the effects of androgens of the liver, not only in terms of size and morphology, but also with respect to enzymic composition fumarase, catalase and D-amino acid oxidase activities were particularly sensitive to androgenic manipulation [32]. Subsequent studies confirmed and extended our understanding of the androgenic responses in liver, but illustrated that they were subject to extreme species variation. No common pattern of hepatic responses to androgens has emerged. 

Schematic model of the glutamate synapse. Gly glycine o-Ser D-serine DAAO D-amino acid oxidase DAOA D-amino acid oxidase activator (aka, G72)...

The operational stability of Trigonopsis variabilis cells with D-amino acid oxidase activity, entrapped in standard and hardened ionotropic gels, was also investigated by means of the FMC [39]. The activity of the biocatalyst packed in the FMC column was continuously monitored by the FMC signal measurement... 

The in vitro effects of thyroid hormones on enzymes in some instances parallel the changes which have been noted in vivo, and in some instances do not. For example, an increased succinoxidase activity can be demonstrated both in vitro and in vivo under the influence of thyroxine. On the other hand, whereas D-amino acid oxidase activity is increased in thyrotoxicosis, thyroxine in vitro inhibits this enzyme. Some of these similarities and discrepancies will be pointed out in the subsequent sections. 

B. D-Amino Acid Oxidases Active Against Cephalo orin C... 

Isogai T, Ono H, ishitani Y, Kojo H, Ueda Y, Kohsaka M. Structure and expression of cDNA for D-amino acid oxidase active against cephalosporin C from Fusariitm solani. J Biochem (Tokyo) 1990 108 1065-1069. 

Miyoshi Y, Hamase K, Tojo Y, Mita M, Kormo R, Zaitsu K. Determination of D-serine and D-alanine in the tissues and physiological fluids of mice with various D-amino-acid oxidase activities using two-dimensional high-performance liquid chromatography with fluorescence detection. J Chromatogr B 2009 877 2506—12. 

Many of the amino acids originally tested by Krebs were racemic mixtures. When naturally occurring L-amino acids became available the oxidase was found to be sterically restricted to the unnatural, D series. [D-serine occurs in worms free and as D-phosphoryl lombricine (Ennor, 1959)]. It could not therefore be the enzyme used in the liver to release NH3 in amino acid metabolism. D-amino acid oxidase was shown by Warburg and Christian (1938) to be a flavoprotein with FAD as its prosthetic group. A few years later Green found an L-amino acid oxidase in liver. It was however limited in its specificity for amino acid substrates and not very active—characteristics which again precluded its central role in deamination. 

Many enzymes, however, do not show temperature compensation in their activities (Eckberg, 1962 Precht, 1964 Vellas, 1965 Hebb etal., 1969 Hazel and Prosser, 1970 Shkorbatov et al., 1972 Hochachka and Somero, 1973 Penny and Goldspink, 1981). Among these are catalase, peroxidase, acid phosphatase, D-amino acid oxidase, choline acetyltransferase, acetylcholinesterase and glucose-6-phosphate dehydrogenase. What is more, the same enzyme can show opposing temperature dependencies when examined in different organs and tissues of fish (Romanenko etal., 1991). 

Madeira C, Freitas ME, Vargas-Lopes C, Wolosker H, Panizzutti R. 2008. Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res 101 ... 

Abstract G72 and G30 constitute a pair of primate-specific genes on complementary strands of human chromosomal 13q33. G72 is proposed to encode a protein that can activate D-amino acid oxidase (DAAO), therefore, named as D-aminoacid oxidase activator (DAOA) (Chumakov et al., 2002). This hypothesis about G72 and DAAO requires substantial further proof (see discussion later), and the neutral name G72 will be used here, although DAOA is widely used in the literature now. The G72/ G30 gene is, at this time, one of the best supported loci for both schizophrenia (SZ) and bipolar disorder (BD) by independent datasets (Craddock et al., 2006 Detera-Wadleigh and McMahon, 2006). Here, we will describe the discovery of gene complex G72/G30, association studies with SZ and BD with a meta-analysis, as well as brief information about the biology of G72/G30. 

List of Abbreviations CD/MRV, Common Disease/Multiple Rare Variants DAAO, D-amino acid oxidase DAOA, D-aminoacid oxidase activator EST, expression sequence tag GEO, Gene Expression Omnibus MAF, minor allele frequency NIMH, National Institute of Mental Health NMDA, N-methyl D-aspartate RT-PCR, reverse transcription-PCR... 

R15. Rudie, N. G., Porter, D. J., and Bright, H. J., Chlorination of an active site tyrosyl residue in D-amino acid oxidase by N-chloro-D-leucine. J. Biol. Chem. 255, 498-508 (1980). 

Figure 13.1 Schematic representation of interactions at the active site of (a) R. gracilis D-amino acid oxidase in complex with CFs-D-alanine (pdb ICOL), (b) C. rhodostoma L-amino acid oxidase in complex with citrate (pdb IF8R), and (c) 6. stearothermophilus alanine racemase (pdb ISFT).

L-Amino acid oxidase is a flavoenzyme that catalyzes the oxidative deamination of L-amino adds. L-Amino acid oxidase activities have been detected in mammals, birds, reptiles, invertebrates, molds, and bacteria [54]. L-Amino acid oxidases show the typical absorption spectrum due to the presence of a molecule of non-covalently bound FAD per subunit (with maxima at 465 and 380nm) they behave like flavoprotein oxidases, as in the case of D-amino acid oxidase. L-Amino add oxidase isolated from rat liver was reported to utilize flavin mononudeotide (FMN) as a co-enzyme, but since it is more active on L-hydroxy acids than on amino adds, it was thus considered as an L-hydroxy add oxidase. Even a partially purified L-amino acid oxidase from turkey Uver appeared to have FMN as a co-factor. 

The X-ray crystallographic structure of Callosdasma rhodostoma L-amino acid oxidase indicates that it is functionally a dimer in which each subunit is constituted by three domains an FAD-binding domain, a substrate-binding domain, and a helical domain [58]. A funnel is formed at the interface between the latter domains and provides substrate access to the active site. Thus, the mode of substrate binding (Figure 13.1b) and access significantly differs between L-amino acid oxidase and D-amino acid oxidase. 

The core requirement for the carbanion mechanism to operate is that an active-site base must abstract the a-carbon hydrogen of the substrate, as a proton, forming a carbanion intermediate (Lederer, 1991). This would then require the equivalent of two electrons to be transferred to the flavin either with or without the formation of a covalent intermediate between the a-carbon and the flavin N-5 (Ghisla and Massey, 1989). With this in mind, it is intriguing to find that the crystal structure of D-amino acid oxidase reveals that there is no residue correctly located to act as the active-site base required for the carbanion mechanism (Mattevi et al., 1996 Mizu-tani et al., 1996). In fact, the crystallographic information available is far more consistent with this enzyme operating a hydride transfer mechanism (Mattevi et al., 1996). If this is correct then the earlier experiments on d-amino acid oxidase, which were claimed to be diagnostic of a carbanion mechanism, are ealled into question. It is important to note that similar experiments were used to provide support for a carbanion mechanism in the ease of flavocytochrome b2-... 

Mattevi, A., Vanoni, M. A., Todone, F., Rizzi, M., Teplyakov, A., Coda, A., Bolognesi, M., and Curti, B., 1996, Crystal structure of D-amino acid oxidase a case of active site mirror-image convergent evolution with flavocytochrome Proc. Natl. Acad. Sci. USA. 93 7496n7501. 

The structures of EX and El were deduced by resolution of El into apoenzyme and free flavin-substrate adduct. The structure of this adduct was determined as 5-cyanoethy 1-1,5-dihydro FAD and that of EX was deduced to be a cationic imine resulting from elimination of NO2" from the initial 5-nitroethy 1-1,5-dihydro FAD adduct formed in the process controlled by k2 by nucleophilic attack of nitroethane carbanion on the position of oxidized flavin. The chemistry of flavin reduction by nitroethane carbanion at the active site of D-amino acid oxidase is given by the following scheme (Equation 19) in which the kinetically important... 

Aminocephalosporanic acid (15, Scheme 9) is an important intermediate in the production of many semisynthetic cephalosporin antibiotics (66, 67). However, direct deacylation of cephalosporin C (13) to 15 by cephalosporin C acy-lase is unfavorable, so an enzymatic process is used involving D-amino acid oxidase (DAAO) oxidation of 13 to A-glutaryl-7-aminocephalosporanic acid (14, GL-7-ACA) followed by deacylation to 15 and glutaric acid, catalyzed by GL-7-ACA acylase from Pseudomonas sp. 130 (Scheme 9) (68, 69). GL-7-ACA acylase underwent pseudo first-order time-dependent inactivation by 7 3-bromoacetyl aminocephalos-poranic acid (16) (70). Dialysis did not regenerate enzyme activity, indicating irreversible inhibition. The rate of inactivation was lowered by the presence of either glutaric acid or 15,... 

Almost all enzymes show a high degree of optical specificity. Thus, there are certain enzymes which catalyse the hydrolysis of same group of substances possessing same optical activity i.e., D-amino acid oxidase acts on D-amino acid and L-amino acid oxidase acts on L-amino acid. Maltase catalyses the hydrolysis of a-but not p- glycosides. 

D-amino acid oxidase is an FAD-linked enzyme, and while there are few D-amino acids that enter the human body the activity of this enzyme in liver is quite high. L-amino acid oxidase is FMN-linked and has broad specificity for the L amino acids. 

FAD + Apo-D-Amino acid oxidase > D-Amino acid oxidase (inactive) (active)... 

---