D-amino acid oxidase: Difference between revisions
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{{short description|Enzyme}} |
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| CAS_number = 9000-88-8 |
| CAS_number = 9000-88-8 |
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| IUBMB_EC_number = 1/4/3/3 |
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| image = Crystal structure of RgDAAO (PDB code 1c0p).png |
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| caption = 3D structure of DAAO from yeast (monomer) |
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| caption = 3D structure of DAAO from yeast (monomer) |
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⚫ | '''D-amino acid oxidase''' ('''DAAO'''; also '''OXDA''' or '''DAMOX''') is an enzyme with the function on a molecular level to [[oxidize]] [[D-amino acid]]s to the corresponding [[Keto acid|α-keto acids]], producing [[ammonia]] and [[hydrogen peroxide]]. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is [[D-Serine]] in the [[central nervous system]]. By targeting this and other D-amino acids in [[vertebrates]], DAAO is important in [[detoxification]]. The role in [[microorganisms]] is slightly different, breaking down D-amino acids to generate energy.<ref name="Physiological functions">{{cite journal | vauthors = Pollegioni L, Piubelli L, Sacchi S, Pilone MS, Molla G | title = Physiological functions of D-amino acid oxidases: from yeast to humans | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 11 | pages = 1373–94 | date = June 2007 | pmid = 17396222 | doi = 10.1007/s00018-007-6558-4 | s2cid = 24070769 | pmc = 11136250 }}</ref> |
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⚫ | DAAO is expressed in a wide range of species from yeasts to human.<ref name="Physiological functions" /> It is not present in plants or in bacteria which instead use [[D-amino acid dehydrogenase]]. DAAO in humans is a candidate susceptibility gene<ref name="SZGene_DAAO">{{cite web | url = http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=131 | author = SZGene database | title = Gene Overview of All Published Schizophrenia-Association Studies for DAAO | date = 28 August 2007 | archive-url = https://web.archive.org/web/20080512122824/http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=131 | archive-date = 2008-05-12 | url-status = dead | work = Schizophrenia Research Forum }}</ref> and together with [[D-amino acid oxidase activator|G72]] may play a role in the [[glutamate hypothesis of schizophrenia|glutamatergic mechanisms of schizophrenia]].<ref name="pmid17250995">{{cite journal | vauthors = Boks MP, Rietkerk T, van de Beek MH, Sommer IE, de Koning TJ, Kahn RS | title = Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia | journal = European Neuropsychopharmacology | volume = 17 | issue = 9 | pages = 567–72 | date = September 2007 | pmid = 17250995 | doi = 10.1016/j.euroneuro.2006.12.003 | s2cid = 24756346 }}</ref> DAAO also plays a role in both biotechnological and medical advancements. [[Risperidone]] and [[sodium benzoate]] are inhibitors of DAAO. |
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⚫ | '''D-amino acid oxidase''' ('''DAAO'''; also |
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⚫ | DAAO is expressed in a wide range of species from yeasts to human.<ref name=" |
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==History== |
==History== |
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In 1935, [[Hans Adolf Krebs]] discovered D-amino acid oxidase after an experiment with [[porcine]] [[kidney]] homogenates and amino acids. Shortly after, [[Otto Heinrich Warburg|Warburg]] and Christian observed the oxidase had a FAD cofactor making it the second [https://en.wiktionary.org/wiki/flavoenzyme flavoenzyme] to be discovered. In the upcoming years other scientists developed and improved the purification procedure for a porcine D-amino acid oxidase.<ref name = AminoAcidOxidase,D->{{cite web|title=Amino Acid Oxidase, D-|url=http://www.worthington-biochem.com/daoff/default.html|website=Worthington Biochemical Corporation|access-date=26 March 2018}}</ref> |
In 1935, [[Hans Adolf Krebs]] discovered D-amino acid oxidase after an experiment with [[porcine]] [[kidney]] homogenates and amino acids. Shortly after, [[Otto Heinrich Warburg|Warburg]] and Christian observed the oxidase had a FAD cofactor making it the second [https://en.wiktionary.org/wiki/flavoenzyme flavoenzyme] to be discovered. In the upcoming years other scientists developed and improved the purification procedure for a porcine D-amino acid oxidase.<ref name = AminoAcidOxidase,D->{{cite web|title=Amino Acid Oxidase, D-|url=http://www.worthington-biochem.com/daoff/default.html|website=Worthington Biochemical Corporation|access-date=26 March 2018}}</ref> |
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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. |
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.<ref name=AminoAcidOxidase,D- /> |
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==Structure and properties== |
==Structure and properties== |
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[[File:HDAAO Head-to-Head Connection.png|thumb|hDAAO |
[[File:HDAAO Head-to-Head Connection.png|thumb|hDAAO head-to-head connection|left]] |
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While D-amino acid oxidase differs to some extent between various [[organisms]], the structure is basically the same across most [[eukaryotes]], excluding plants. This enzyme is a flavoprotein belonging to the [[FAD dependent oxidoreductase family]], and acts on the CH-NH<sub>2</sub> group of D-amino acid donors with oxygen as acceptor. It is also considered a peroxisomal [[enzyme]] containing [[flavin adenine dinucleotide|FAD]] as a cofactor.<ref name="Physiological functions" /> Each DAO [[monomer]] has an [[FAD]]-[[binding domain]] (FBD) containing a [[ |
While D-amino acid oxidase differs to some extent between various [[organisms]], the structure is basically the same across most [[eukaryotes]], excluding plants. This enzyme is a flavoprotein belonging to the [[FAD dependent oxidoreductase family]], and acts on the CH-NH<sub>2</sub> group of D-amino acid donors with oxygen as acceptor. It is also considered a peroxisomal [[enzyme]] containing [[flavin adenine dinucleotide|FAD]] as a cofactor.<ref name="Physiological functions" /> Each DAO [[monomer]] has an [[FAD]]-[[binding domain]] (FBD) containing a [[Rossmann fold]], and a [[substrate (chemistry)|substrate]]-binding domain (SBD) that also forms an interface with the other monomer in the protein.<ref name="Physiological functions" /> DAO exists as a [[Dimer (chemistry)|dimer]], with each monomer containing both an FBD and SBD. Each monomer is composed of 347 [[amino acids]] in human DAO, though among other eukaryotes the protein can range from 345 to 368 amino acids long.<ref name="Physiological functions" /> In human DAO, the two monomers are connected in a head-to-head fashion.<ref name="Competitive Inhibitors">{{cite journal | vauthors = Molla G | title = Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase | journal = Frontiers in Molecular Biosciences | volume = 4 | issue = 80 | pages = 80 | date = 27 November 2017 | pmid = 29250527 | pmc = 5715370 | doi = 10.3389/fmolb.2017.00080 | doi-access = free }}</ref> DAO of other organisms, such as yeast, can be present as head-to-tail dimers.<ref name="Competitive Inhibitors" /> The hDAAO gene is found on chromosome 12 and contains 11 exons.<ref name="Physiological functions" /> |
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DAO is capable of [[Organic redox reaction|reducing]] oxygen quickly |
DAO is capable of [[Organic redox reaction|reducing]] oxygen quickly, and when reduced can stabilize anionic red [[semiquinone]], and it is capable of forming a [[covalent bond]] with [[sulfites]]. These are all typical properties associated with [[flavoproteins]].<ref name="Physiological functions" /> Human DAAO has slightly different properties from other DAAO molecules, including a weaker ability to bind FAD and decreased [[rate of reaction]] for some molecules, such as [[Flavin group|flavin]].<ref name="Physiological functions" /> |
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==Actions in the brain== |
==Actions in the brain== |
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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.<ref name="Neurobiology of DAO">{{cite journal | vauthors = Verrall L, Burnet PW, Betts JF, Harrison PJ | title = The neurobiology of D-amino acid oxidase and its involvement in schizophrenia | journal = Molecular Psychiatry | volume = 15 | issue = 2 | pages = 122–37 | date = February 2010 | pmid = 19786963 | pmc = 2811712 | doi = 10.1038/mp.2009.99 }}</ref> 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. |
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.<ref name="Neurobiology of DAO">{{cite journal | vauthors = Verrall L, Burnet PW, Betts JF, Harrison PJ | title = The neurobiology of D-amino acid oxidase and its involvement in schizophrenia | journal = Molecular Psychiatry | volume = 15 | issue = 2 | pages = 122–37 | date = February 2010 | pmid = 19786963 | pmc = 2811712 | doi = 10.1038/mp.2009.99 }}</ref> 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.<ref name="Neurobiology of DAO" /> The consensus is that DAO is produced and is active in glial cells, most specifically in cerebellar type-1 and type-2 astrocytes,<ref name="Physiological functions" /> and the D-serine amino acid that is produced by DAO in these cells has been shown to increase synaptic [[NMDA receptor]] activity.<ref name="Physiological functions" /> |
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==Impact on schizophrenia== |
==Impact on schizophrenia== |
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{{ |
{{Further|Schizophrenia#Mechanisms}} |
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There is evidence to show that schizophrenia, as a neural phenomenon, is associated with both hyper- and hypoglutamatergic function, mediated by NMDA receptors.<ref>{{cite journal | vauthors = Olney JW, Newcomer JW, Farber NB | title = NMDA receptor hypofunction model of schizophrenia | journal = Journal of Psychiatric Research | volume = 33 | issue = 6 | pages = 523–33 | date = November 1999 | pmid = 10628529 | doi = 10.1016/s0022-3956(99)00029-1 }}</ref> Dysfunction of NMDA receptors, and the corresponding hypoglutamatergic signaling, produces overstimulation ionotropic receptors and leads to excitotoxicity.<ref name=":0">{{cite journal | vauthors = Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG | title = Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection | journal = Pharmacological Reviews | volume = 60 | issue = 3 | pages = 358–403 | date = September 2008 | pmid = 18922967 | pmc = 4821196 | doi = 10.1124/pr.107.00107 }}</ref> |
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There is evidence to show that schizophrenia, as a neural phenomenon, is caused by the inappropriate activity of NMDA receptors and the related increase in [[glutamate]] activity associated with NMDA receptors. <ref name="Physiological functions" /> |
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[[File:SchizophreniaBrain.jpg|thumb|SchizophreniaBrain]] |
[[File:SchizophreniaBrain.jpg|thumb|SchizophreniaBrain]] |
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It has been shown that |
It has been shown that decreased DAO activity leads to an increase in NMDA activity in the [[hypothalamus]] .<ref name="Physiological functions"/> Inhibition of DAO leads to the increase of D-serine levels which act as agonists at the NMDAR.<ref name=":0" /> |
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A study confirmed the increased NMDA activity and showed increased DAO activity in the [[cerebellum]] of schizophrenia subjects.<ref name="Neurobiology of DAO" /> 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.<ref name="Neurobiology of DAO" /> |
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==Regulation== |
==Regulation== |
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Bassoon protein<ref>{{cite web |title=BSN - Protein bassoon - Homo sapiens (Human) - BSN gene & protein |url=https://www.uniprot.org/uniprot/Q9UPA5 |website=www.uniprot.org |language=en}}</ref> and pLG72, are the current known proteins to physically interact and modulate human DAAO.<ref name="Competitive Inhibitors" /> plG72 is the product of the primate-specific G72 gene, and higher levels of both were observed in schizophrenia patients. Interaction of plG72 with hDAAO was observed to cause a time-dependent inactivation with the oxidase.<ref>{{cite journal | vauthors = Pollegioni L, Piubelli L, Molla G, Rosini E | title = D-Amino Acid Oxidase-pLG72 Interaction and D-Serine Modulation | journal = Frontiers in Molecular Biosciences | volume = 5 | pages = 3 | date = 2018 | pmid = 29417050 | pmc = 5787542 | doi = 10.3389/fmolb.2018.00003 | doi-access = free }}</ref> This is believed to be caused by plG72 binding limiting the amount of the enzyme that is [[Catalysis|catalytically]] competent, and can be negated by the cofactor or any active-site ligands. The plG72 structure is not fully determined so the specific physical interaction with hDAAO is not completely understood as well. Experiments with the basson protein and hDAAO has resulted with a decrease in enzymatic activity similar to plG72. Researchers suspect the bassoon protein prevents D-Serine depletion particularly in the [[presynaptic]] neuron.<ref name="Competitive Inhibitors" /> |
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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 [[competitive inhibition]]. All of these compounds have two similar, main portions.<ref name="Competitive Inhibitors" /> The first portion is the planar portion which interacts with the active site of hDAAO. The planar site’s chemical structure is formed by one or two fused [[Cyclic compound|rings]] and must have a negatively charged [[Carboxylic acid|carboxylic]] group. The second portion is the [[Substrate (biochemistry)|substrate]] chain, which can participate in the active zone or entrance of the enzyme. |
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 [[competitive inhibition]]. All of these compounds have two similar, main portions.<ref name="Competitive Inhibitors" /> The first portion is the planar portion which interacts with the active site of hDAAO. The planar site’s chemical structure is formed by one or two fused [[Cyclic compound|rings]] and must have a negatively charged [[Carboxylic acid|carboxylic]] group. The second portion is the [[Substrate (biochemistry)|substrate]] chain, which can participate in the active zone or entrance of the enzyme. Furthermore, the different compounds are divided into multiple categories (classical, novel, second generation, third generation) depending on the chemical structures. An example of a compound is [[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.<ref name="Competitive Inhibitors" /> |
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==Applications== |
==Applications== |
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==== Cephalosporin synthesis ==== |
==== Cephalosporin synthesis ==== |
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D-amino acid oxidase is used in [[biotechnology]] primarily to produce antibiotics called [[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 |
D-amino acid oxidase is used in [[biotechnology]] primarily to produce antibiotics called [[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.<ref name="D-Amino acid oxidase: new findings" /> |
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==== D-amino acid biosensor ==== |
==== D-amino acid biosensor ==== |
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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 |
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 [[enantiomer]]s 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.<ref name="D-Amino Acid Oxidase: Physiological Role and Applications">{{cite journal | vauthors = Khoronenkova SV, Tishkov VI | title = D-amino acid oxidase: physiological role and applications | journal = Biochemistry. Biokhimiia | volume = 73 | issue = 13 | pages = 1511–8 | date = December 2008 | pmid = 19216715 | doi = 10.1134/S0006297908130105 | s2cid = 18587080 }}</ref> There is no evidence to prove that D-amino acids are toxic, but it raises many possible concerns whether some foods are toxic. |
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===Medical=== |
===Medical=== |
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==== Cancer treatment ==== |
==== Cancer treatment ==== |
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RgDAAO is used in a process called [[GDEPT|gene-directed enzyme prodrug therapy (GDEPT)]] to treat tumors in cancer patients. This treatment uses RgDAAO as the enzyme and [[D-alanine]] as a substrate to create a reactive oxygen species |
RgDAAO is used in a process called [[GDEPT|gene-directed enzyme prodrug therapy (GDEPT)]] to treat tumors in cancer patients. This treatment uses RgDAAO as the enzyme and [[D-alanine]] as a substrate to create a reactive oxygen species H<sub>2</sub>O<sub>2</sub> as a product. H<sub>2</sub>O<sub>2</sub> permeates through tumor cells and damages [[biopolymers]]. The damage done by [[H2O2|H<sub>2</sub>O<sub>2</sub>]] creates a cytotoxic metabolite from a nontoxic [[prodrug]] within the tumor cells, which then creates a toxic substance in those cells alone.<ref name="D-Amino acid oxidase: new findings">{{cite journal | vauthors = Pilone MS | title = D-Amino acid oxidase: new findings | journal = Cellular and Molecular Life Sciences | volume = 57 | issue = 12 | pages = 1732–47 | date = November 2000 | pmid = 11130179 | doi = 10.1007/PL00000655 | s2cid = 12644310 | pmc = 11147001 }}</ref> 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.<ref name="D-Amino Acid Oxidase: Physiological Role and Applications" /> |
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==== Therapeutic treatments ==== |
==== Therapeutic treatments ==== |
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D-amino acid oxidase is used in therapeutic treatments such as regulation of hormones, regulation of [[hypertension]], treatment of schizophrenia, |
D-amino acid oxidase is used in therapeutic treatments such as regulation of hormones, regulation of [[hypertension]], treatment of schizophrenia, treatment of psychiatric and cognitive disorders, and possible pain reduction. Changing the amount of D-amino acid oxidase transporters with the use of drugs has therapeutic effects on schizophrenia.<ref name="The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors">{{cite journal | vauthors = Smith SM, Uslaner JM, Hutson PH | title = The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors | journal = The Open Medicinal Chemistry Journal | volume = 4 | pages = 3–9 | date = May 2010 | pmid = 20648222 | pmc = 2905773 | doi = 10.2174/1874104501004020003 | doi-broken-date = 2024-03-28 |doi-access=free}}</ref> D-amino acid oxidase regulates D-Aspartate, which regulates the secretion of [[melatonin]], [[prolactin]], [[testosterone]], [[luteinizing hormone]] and [[growth hormone]]. By regulating D-amino acid oxidase, D-Aspartate can also be regulated and control hormone secretion. Increased D-amino acid oxidase activity has been correlated with psychiatric and cognitive disorders, so reducing D-amino acid oxidase can have therapeutic effects on these disorders. D-amino acid oxidase helps produce L-6-hydroxynorleucine, which then generates [[Omapatrilat]]. Omapatrilat inhibits [[angiotensin-converting enzyme]] and [[neutral endopeptidase]] and effectively reduces hypertension. D-amino acid oxidase also may have an effect on pain stimuli, but it is not confirmed yet.<ref name="D-Amino Acid Oxidase: Physiological Role and Applications" /> |
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== See also == |
== See also == |
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*[[DAO (disambiguation)|DAO]] |
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*[[DAOA-AS1]] |
*[[DAOA-AS1]] |
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*[[D-amino acid dehydrogenase]] |
*[[D-amino acid dehydrogenase]] |
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== References == |
== References == |
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{{Reflist}} |
{{Reflist|32em}} |
Latest revision as of 08:49, 10 June 2024
D-amino-acid oxidase | |||||||||
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![]() 3D structure of DAAO from yeast (monomer) | |||||||||
Identifiers | |||||||||
EC no. | 1.4.3.3 | ||||||||
CAS no. | 9000-88-8 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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D-amino-acid oxidase | |||||||
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Identifiers | |||||||
Symbol | DAO (DAAO) | ||||||
NCBI gene | 1610 | ||||||
HGNC | 2671 | ||||||
OMIM | 124050 | ||||||
RefSeq | NM_001917 | ||||||
UniProt | P14920 | ||||||
Other data | |||||||
EC number | 1.4.3.3 | ||||||
Locus | Chr. 12 q24 | ||||||
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D-amino acid oxidase (DAAO; also OXDA or DAMOX) is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding α-keto acids, producing ammonia and hydrogen peroxide. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is D-Serine in the central nervous system. By targeting this and other D-amino acids in vertebrates, DAAO is important in detoxification. The role in 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
[edit]In 1935, Hans Adolf Krebs discovered D-amino acid oxidase after an experiment with 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
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/2/29/HDAAO_Head-to-Head_Connection.png/220px-HDAAO_Head-to-Head_Connection.png)
While D-amino acid oxidase differs to some extent between various organisms, the structure is basically the same across most eukaryotes, excluding plants. This enzyme is a flavoprotein belonging to the FAD dependent oxidoreductase family, and acts on the CH-NH2 group of D-amino acid donors with oxygen as acceptor. It is also considered a peroxisomal enzyme containing FAD as a cofactor.[1] Each DAO monomer has an FAD-binding domain (FBD) containing a Rossmann fold, and a substrate-binding domain (SBD) that also forms an interface with the other monomer in the protein.[1] DAO exists as a dimer, with each monomer containing both an FBD and SBD. Each monomer is composed of 347 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 reducing oxygen quickly, and when reduced can stabilize anionic red semiquinone, and it is capable of forming a covalent bond with sulfites. These are all typical properties associated with flavoproteins.[1] Human DAAO has slightly different properties from other DAAO molecules, including a weaker ability to bind FAD and decreased rate of reaction for some molecules, such as flavin.[1]
Actions in the brain
[edit]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
[edit]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]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/14/SchizophreniaBrain.jpg/220px-SchizophreniaBrain.jpg)
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
[edit]Bassoon protein[9] and pLG72, are the current known proteins to physically interact and modulate human DAAO.[5] plG72 is the product of the primate-specific G72 gene, and higher levels of both were observed in schizophrenia patients. Interaction of plG72 with hDAAO was observed to cause a time-dependent inactivation with the oxidase.[10] This is believed to be caused by plG72 binding limiting the amount of the enzyme that is catalytically competent, and can be negated by the cofactor or any active-site ligands. The plG72 structure is not fully determined so the specific physical interaction with hDAAO is not completely understood as well. Experiments with the basson protein and hDAAO has resulted with a decrease in enzymatic activity similar to plG72. Researchers suspect the bassoon protein prevents D-Serine depletion particularly in the 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 competitive inhibition. All of these compounds have two similar, main portions.[5] The first portion is the planar portion which interacts with the active site of hDAAO. The planar site’s chemical structure is formed by one or two fused rings and must have a negatively charged carboxylic group. The second portion is the substrate chain, which can participate in the active zone or entrance of the enzyme. Furthermore, the different compounds are divided into multiple categories (classical, novel, second generation, third generation) depending on the chemical structures. An example of a compound is 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
[edit]Biotechnology
[edit]Cephalosporin synthesis
[edit]D-amino acid oxidase is used in biotechnology primarily to produce antibiotics called 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
[edit]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
[edit]Cancer treatment
[edit]RgDAAO is used in a process called gene-directed enzyme prodrug therapy (GDEPT) to treat tumors in cancer patients. This treatment uses RgDAAO as the enzyme and D-alanine as a substrate to create a reactive oxygen species H2O2 as a product. H2O2 permeates through tumor cells and damages biopolymers. The damage done by 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
[edit]D-amino acid oxidase is used in therapeutic treatments such as regulation of hormones, regulation of hypertension, treatment of schizophrenia, treatment of psychiatric and cognitive disorders, and possible pain reduction. Changing the amount of D-amino acid oxidase transporters with the use of drugs has therapeutic effects on schizophrenia.[13] D-amino acid oxidase regulates D-Aspartate, which regulates the secretion of melatonin, prolactin, testosterone, luteinizing hormone and growth hormone. By regulating D-amino acid oxidase, D-Aspartate can also be regulated and control hormone secretion. Increased D-amino acid oxidase activity has been correlated with psychiatric and cognitive disorders, so reducing D-amino acid oxidase can have therapeutic effects on these disorders. D-amino acid oxidase helps produce L-6-hydroxynorleucine, which then generates Omapatrilat. Omapatrilat inhibits angiotensin-converting enzyme and 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
[edit]- DAOA-AS1
- D-amino acid dehydrogenase
- D-amino acid oxidase activator
- D-aspartate oxidase
- Diamine oxidase
External links
[edit]- D-Amino-Acid+Oxidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- http://www.calzyme.com/commerce/catalog/spcategory.jsp?category_id=1043
References
[edit]- ^ a b c d e f g h i j k Pollegioni L, Piubelli L, Sacchi S, Pilone MS, Molla G (June 2007). "Physiological functions of D-amino acid oxidases: from yeast to humans". Cellular and Molecular Life Sciences. 64 (11): 1373–94. doi:10.1007/s00018-007-6558-4. PMC 11136250. PMID 17396222. S2CID 24070769.
- ^ 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.
- ^ Boks MP, Rietkerk T, van de Beek MH, Sommer IE, de Koning TJ, Kahn RS (September 2007). "Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia". European Neuropsychopharmacology. 17 (9): 567–72. doi:10.1016/j.euroneuro.2006.12.003. PMID 17250995. S2CID 24756346.
- ^ a b "Amino Acid Oxidase, D-". Worthington Biochemical Corporation. Retrieved 26 March 2018.
- ^ a b c d e f Molla G (27 November 2017). "Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase". Frontiers in Molecular Biosciences. 4 (80): 80. doi:10.3389/fmolb.2017.00080. PMC 5715370. PMID 29250527.
- ^ a b c d Verrall L, Burnet PW, Betts JF, Harrison PJ (February 2010). "The neurobiology of D-amino acid oxidase and its involvement in schizophrenia". Molecular Psychiatry. 15 (2): 122–37. doi:10.1038/mp.2009.99. PMC 2811712. PMID 19786963.
- ^ Olney JW, Newcomer JW, Farber NB (November 1999). "NMDA receptor hypofunction model of schizophrenia". Journal of Psychiatric Research. 33 (6): 523–33. doi:10.1016/s0022-3956(99)00029-1. PMID 10628529.
- ^ a b Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, et al. (September 2008). "Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection". Pharmacological Reviews. 60 (3): 358–403. doi:10.1124/pr.107.00107. PMC 4821196. PMID 18922967.
- ^ "BSN - Protein bassoon - Homo sapiens (Human) - BSN gene & protein". www.uniprot.org.
- ^ Pollegioni L, Piubelli L, Molla G, Rosini E (2018). "D-Amino Acid Oxidase-pLG72 Interaction and D-Serine Modulation". Frontiers in Molecular Biosciences. 5: 3. doi:10.3389/fmolb.2018.00003. PMC 5787542. PMID 29417050.
- ^ a b Pilone MS (November 2000). "D-Amino acid oxidase: new findings". Cellular and Molecular Life Sciences. 57 (12): 1732–47. doi:10.1007/PL00000655. PMC 11147001. PMID 11130179. S2CID 12644310.
- ^ a b c Khoronenkova SV, Tishkov VI (December 2008). "D-amino acid oxidase: physiological role and applications". Biochemistry. Biokhimiia. 73 (13): 1511–8. doi:10.1134/S0006297908130105. PMID 19216715. S2CID 18587080.
- ^ Smith SM, Uslaner JM, Hutson PH (May 2010). "The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors". The Open Medicinal Chemistry Journal. 4: 3–9. doi:10.2174/1874104501004020003 (inactive 2024-03-28). PMC 2905773. PMID 20648222.
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