Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates

Abstract

d-Amino-acid oxidase (DAO) catalyzes the oxidative deamination of d-amino acids. DAO is present in a wide variety of organisms and has important roles. Here, we review the distribution and physiological substrates of mouse DAO. Mouse DAO is present in the kidney, brain, and spinal cord, like DAOs in other mammals. However, in contrast to other animals, it is not present in the mouse liver. Recently, DAO has been detected in the neutrophils, retina, and small intestine in mice. To determine the physiological substrates of mouse DAO, mutant mice lacking DAO activity are helpful. As DAO has wide substrate specificity and degrades various d-amino acids, many d-amino acids accumulate in the tissues and body fluids of the mutant mice. These amino acids are d-methionine, d-alanine, d-serine, d-leucine, d-proline, d-phenylalanine, d-tyrosine, and d-citrulline. Even in wild-type mice, administration of DAO inhibitors elevates D-serine levels in the plasma and brain. Among the above d-amino acids, the main physiological substrates of mouse DAO are d-alanine and d-serine. These two d-amino acids are most abundant in the tissues and body fluids of mice. d-Alanine derives from bacteria and produces bactericidal reactive oxygen species by the action of DAO. d-Serine is synthesized by serine racemase and is present especially in the central nervous system, where it serves as a neuromodulator. DAO is responsible for the metabolism of d-serine. Since DAO has been implicated in the etiology of neuropsychiatric diseases, mouse DAO has been used as a representative model. Recent reports, however, suggest that mouse DAO is different from human DAO with respect to important properties.

d-Amino acids and kidney diseases

“…Another enzymatic regulator is DAO [1]. DAO oxidizes d-serine and generates 2-hydroxy-pyruvate along with hydrogen peroxide and ammonia [27,28].…”

“…While SR is predominant in the forebrain, DAO is expressed more broadly [27,28]. DAO is most abundant in the kidney.…”

Advances in D-Amino Acids in Neurological Research

“…The relative effectiveness of D-alanine in treating schizophrenia is blunted by the fact that the body quickly metabolizes it after administration [ 29 ]. These results have triggered significant interest in the body’s ability to modulate D-alanine, and until recently it has been taken as fact that D-alanine is absorbed from bacteria and degraded by DAAO [ 28 , 29 , 30 , 33 ]. This has meant that there has been a great deal of interest in DAAO inhibitors to help bolster D-alanine levels in schizophrenic patients [ 28 , 29 , 30 ].…”

“…These results have triggered significant interest in the body’s ability to modulate D-alanine, and until recently it has been taken as fact that D-alanine is absorbed from bacteria and degraded by DAAO [ 28 , 29 , 30 , 33 ]. This has meant that there has been a great deal of interest in DAAO inhibitors to help bolster D-alanine levels in schizophrenic patients [ 28 , 29 , 30 ]. Indeed, this seems to be the case in mice [ 28 ], but experiments in dogs and monkeys have shown no significant difference between animals taking DAAO inhibitors and those taking nothing [ 29 , 30 ].…”

“…The primary method for eliminating D-amino acids is that they are transported to the kidneys and metabolized before being excreted [ 93 , 94 , 95 ]. While both DAAO and DDO are expressed in the brain, the highest levels of expression for DAAO are in the liver and kidneys, and the highest level of expression for DDO is in the heart [ 28 , 96 ]. Interesting, there have been recent studies showing that amino acids such as D-alanine are simply excreted by the kidneys rather than being metabolized, calling into question the centrality of DAAO in D-amino acid regulation [ 29 , 30 , 95 ].…”