D-amino acid oxidase

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Not to be confused with Diamine oxidase or D-aspartate oxidase.
D-amino-acid oxidase
ExPASy
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KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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NCBIproteins
D-amino-acid oxidase
Identifiers
SymbolDAO (DAAO)
Chr. 12 q24
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StructuresSwiss-model
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D-amino acid oxidase (DAAO; also OXDA, DAMOX) is an enzyme with the function on a molecular level to

microorganisms is slightly different, breaking down D-amino acids to generate energy.[1]

DAAO is expressed in a wide range of species from yeasts to human.[1] It is not present in plants or in bacteria which instead use D-amino acid dehydrogenase. DAAO in humans is a candidate susceptibility gene[2] and together with G72 may play a role in the glutamatergic mechanisms of schizophrenia.[3] DAAO also plays a role in both biotechnological and medical advancements. Risperidone and sodium benzoate are inhibitors of DAAO.

D-amino acid oxidase is different from diamine oxidase that are both sometimes referred to as DAO.

History

In 1935,

porcine kidney homogenates and amino acids. Shortly after, Warburg and Christian observed the oxidase had a FAD cofactor making it the second flavoenzyme to be discovered. In the upcoming years other scientists developed and improved the purification procedure for a porcine D-amino acid oxidase.[4]

In 1983, inhibitors for the oxidase were discovered. In 2006, the 3D structure of the oxidase was published. Currently, the link between human D-amino acid oxidase (hDAAO) activity and schizophrenia is being researched.[4]

Structure and properties

hDAAO head-to-head connection

While D-amino acid oxidase differs to some extent between various

amino acids in human DAO, though among other eukaryotes the protein can range from 345 to 368 amino acids long.[1] In human DAO, the two monomers are connected in a head-to-head fashion.[5] DAO of other organisms, such as yeast, can be present as head-to-tail dimers.[5] The hDAAO gene is found on chromosome 12 and contains 11 exons.[1]

DAO is capable of

rate of reaction for some molecules, such as flavin.[1]

Actions in the brain

DAO acts in the brain to oxidize specific D-amino acids using the FAD region (flavin adenine dinucleotide region) and is commonly thought to be produced in the hindbrain, although there is new evidence of DAO expression in the forebrain as well.[6] The DAO present in the forebrain seems to be inactive, however, causing speculation on the topic of DAO function in the forebrain as opposed to the hindbrain where the function is more well-known.[6] The consensus is that DAO is produced and is active in glial cells, most specifically in cerebellar type-1 and type-2 astrocytes,[1] and the D-serine amino acid that is produced by DAO in these cells has been shown to increase synaptic NMDA receptor activity.[1]

Impact on schizophrenia

Further information: Schizophrenia § Mechanisms

There is evidence to show that schizophrenia, as a neural phenomenon, is associated with both hyper- and hypoglutamatergic function, mediated by NMDA receptors.[7] Dysfunction of NMDA receptors, and the corresponding hypoglutamatergic signaling, produces overstimulation ionotropic receptors and leads to excitotoxicity.[8]

SchizophreniaBrain

It has been shown that decreased DAO activity leads to an increase in NMDA activity in the hypothalamus .[1] Inhibition of DAO leads to the increase of D-serine levels which act as agonists at the NMDAR.[8]

A study confirmed the increased NMDA activity and showed increased DAO activity in the cerebellum of schizophrenia subjects.[6] The genetic background of DAO involvement in schizophrenia is highly debated, and no compulsatory evidence has been found for DAO genes being strongly linked to schizophrenia. Although, the G72 gene, which reportedly encodes the D-amino acid oxidase activator, may be involved in the development of schizophrenia.[6]

Regulation

Bassoon protein

presynaptic neuron.[5]

Additionally, researchers focused on compounds that could act as hDAAO inhibitors. Over 500 different compounds have been observed in vitro/in vivo to act as inhibitors on the oxidase and most of them do by

benzoate, which is a classical inhibitor. The carboxylic group of benzoate interacts with Arg238, and the aromatic interacts with Tyr224 on the active zone of the oxidase.[5]

Applications

Biotechnology

Cephalosporin synthesis

D-amino acid oxidase is used in

cephalosporins. The use of D-amino acid oxidase for the creation of antibiotics is a patented production of antibiotics and started in 1970. Originally the D-amino acid oxidase used in this process was taken from a pig’s kidney and was given the name pkDAAO. PkDAAO is very unstable throughout the processes of antibiotic synthesis and therefore gave a low yield of antibiotics. Through continued research a more successful form of D-amino acid oxidase was discovered from a yeast species named Rhodotorula gracilis and therefore was named RgDAAO. RgDAAO is now used as the primary D-amino acid oxidase used in cephalosporin antibiotics because the immobilization on commercial ion exchange resins creates a more stable system that yields much higher amounts of antibiotics.[11]

D-amino acid biosensor

D-amino acid oxidase reacts to D-amino acids and can be used to detect the amount of D-amino acids in foods to act as a biosensor. This is important due to the effects of D-amino acids in the D-isomer or multiple enantiomers present in food has on the nutritional value. The more D-isomer or multiple enantiomers present in food, the lower the nutritional value of the food is, so using D-amino acid oxidase to detect these allows for an increase in selection for nutritionally valuable foods.[12] There is no evidence to prove that D-amino acids are toxic, but it raises many possible concerns whether some foods are toxic.

Medical

Cancer treatment

RgDAAO is used in a process called

H2O2 creates a cytotoxic metabolite from a nontoxic prodrug within the tumor cells, which then creates a toxic substance in those cells alone.[11] This process is beneficial for cancer patients, because this treatment is toxic only to tumor cells, while chemotherapy is toxic to all cells in the patient's body. D-amino acid oxidase also plays a role in 4-Methylthio-2-oxobutyric acid (MTOBA) production, which is used as an anticancer drug which induces apoptosis of cancer cells.[12]

Therapeutic treatments

D-amino acid oxidase is used in therapeutic treatments such as regulation of hormones, regulation of

neutral endopeptidase and effectively reduces hypertension. D-amino acid oxidase also may have an effect on pain stimuli, but it is not confirmed yet.[12]

See also

External links

References

  1. ^
    S2CID 24070769
    .
  2. ^ SZGene database (28 August 2007). "Gene Overview of All Published Schizophrenia-Association Studies for DAAO". Schizophrenia Research Forum. Archived from the original on 2008-05-12.
  3. S2CID 24756346
    .
  4. ^ a b "Amino Acid Oxidase, D-". Worthington Biochemical Corporation. Retrieved 26 March 2018.
  5. ^
    PMID 29250527
    .
  6. ^
    PMID 19786963
    .
  7. PMID 10628529
    .
  8. ^
    PMID 18922967
    .
  9. ^ "BSN - Protein bassoon - Homo sapiens (Human) - BSN gene & protein". www.uniprot.org.
  10. PMID 29417050
    .
  11. ^
    S2CID 12644310
    .
  12. ^
    S2CID 18587080
    .
  13. PMID 20648222.{{cite journal}}: CS1 maint: DOI inactive as of March 2024 (link
    )
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