ABHD12

Last updated
ABHD12
Identifiers
Aliases ABHD12 , ABHD12A, BEM46L2, C20orf22, PHARC, dJ965G21.2, abhydrolase domain containing 12, habhydrolase domain containing 12, lysophospholipase
External IDs OMIM: 613599 MGI: 1923442 HomoloGene: 22910 GeneCards: ABHD12
Orthologs
SpeciesHumanMouse
Entrez

26090

76192

Ensembl

ENSG00000100997

ENSMUSG00000032046

UniProt

Q8N2K0

Q99LR1

RefSeq (mRNA)

NM_001042472
NM_015600

NM_024465
NM_001356549
NM_001356550

RefSeq (protein)

NP_001035937
NP_056415

NP_077785
NP_001343478
NP_001343479

Location (UCSC) Chr 20: 25.29 – 25.39 Mb Chr 2: 150.67 – 150.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. [5] It is responsible for about 9% of brain 2-AG hydrolysis. [5] Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain. [5] ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS). [6]

Contents

Protein structure

ABHD12 is a ≈45 kDa integrated membrane glycoprotein, with an active site proposed to face into the extracellular space. [7]

Currently, the crystal structure of ABHD12 is not known.

Function

ABHD12 is a lysophosphatidylserine (lysoPS) lipase responsible for regulation of immune and neurological processes, and shown to act on the endocannabinoid arachidonoylglycerol (AG) as a monoacylglycerol lipase. [8] [9] Endocannabinoids are associated with a range of physiological processes. ABHD12 acts on 2-AG, and accounts for approximately 9% of 2-AG hydrolysis in the brain. [5] Along with MAGL and ABHD6, ABHD12 is responsible for 99% of 2-AG hydrolysis in the brain, [7] and has also been shown to act on the 1(3)-AG isomer. [9] Based on the extracellular face of the ABHD12 active site and its ability to act on multiple isomeric substrates, ABHD12 has been suggested to act as a guard to the extracellular 2-AG-CB2R signalling pathway in microglia, and peripheral 2-AG signalling, however this has not been confirmed. [9] [5]

ABHD12 transcription is abundant in the brain, specifically microglia, but has also been identified in peripheral cell types like macrophages and osteoclasts. [10] Murine models have shown ABHD12 plays a role in regulation of lysophosphatidylserine pathways in the brain. [11]

Clinical significance

Mutations that compromise the catalytic activity of ABHD12 have been causally linked to the rare neurodegenerative disease PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataracts) [10] and a small proportion of retinitis pigmentosa. [12] [13]

History

Identification of ABHD12 was first reported in genetic profiling of autosomal recessive retinitis pigmentosa in 1995. [12] In 2010, mutations in ABHD12 were reported as a causal link for the neurodegenerative disease PHARC . [10]

Mutations

Mutations in ABHD12 are associated with the rare neurodegenerative disorder PHARC, as well as retinitis pigmentosa. Null mutations have been shown to lead to development of PHARC, while other mutations can result in a range of phenotypes, from non-syndromic retinal degeneration to PHARC. [14]

Currently, PHARC has been identified in at least 27 individuals, with 15 identified loss of function variants of ABHD12, [15] comprising four nonsense, four missense, four frameshift and one splicing mutation. [10] [14] [15] [16] [17] [18] [19] ABHD12 missense mutations have been identified in individuals with retinitis pigmentosa, and a growing range of phenotypes associated with ABHD12 mutations from PHARC to non-syndromic retinal degeneration are being discovered. [14] [18]

In vitro, enzymatic activity of ABHD12 can be eliminated by site mutation the residues Serine-246, Aspartate-333, or Histidine-372, which form a catalytic triad in the hydrolase domain. [9]

Inhibitors

Inhibitors of ABHD12 have been identified. [6] Orlistat (tetrahydrolipstatin; THL) and methyl arachidonyl fluorophosphonate (MAFP), so-called "universal lipase/serine hydrolase inhibitors" that are extremely non-selective enzyme inhibitors, were found to inhibit ABHD12. [6] Selective reversible inhibitors have also been identified, including betulinic acid, maslinic acid, oleanolic acid, and ursolic acid. [6]

Models

The α/β hydrolase domain including lipase motif and catalytic triad is conserved between murine and human ABHD12. [11]

Based on the observation of ABHD12 mutation in PHARC affected subjects, PHARC cell lines have been considered as human models of ABHD12 knockout. [10]

Mouse knockout (ABHD12 -/-) models demonstrate cerebellar microgliosis, motor and auditory impairment, alongside elevated neuroinflammation with progression associated with age. These characteristics are considered PHARC-like phenotypes as a murine model for human PHARC, however the mouse knockout model doesn't demonstrate ocular or myelination defects, or early onset typical of PHARC. [11] The ABHD -/- murine model shows increased long-chain lysoPS accumulation in the brain suggesting lysoPS signalling contributes to PHARC-like pathology. [11]

A zebrafish knockdown (+/-) model has been developed which demonstrates ophthalmic defects including microphthalmia, lack of lens clarity, and disrupted retina architecture. [15]

Interactions

Elevated lysoPS accumulation in ABHD12 knockout mice suggests lysoPS as an in vivo substrate of ABHD12. [11] Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor of ABHD16A. [20]

In vitro studies demonstrate enzymatic hydrolysis of monoacylglycerol long lipid chains by ABHD12. ABHD12 can use both 1(3)-AG and 2-AG as substrates at comparable enzymatic rates. [9]

ABHD12 has been shown to be associated with AMPA type glutamate receptors in the brains of rats. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

<span class="mw-page-title-main">URB754</span> Chemical compound

URB754 was originally reported by Piomelli et al. to be a potent, noncompetitive inhibitor of monoacylglycerol lipase (MGL). However, recent studies have shown that URB754 failed to inhibit recombinant MGL, and brain FAAH activity was also resistant to URB754. In a later study by Piomelli et al., the MGL-inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane.

<span class="mw-page-title-main">Endocannabinoid system</span> Biological system of neurotransmitters

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Monoacylglycerol lipase</span> Class of enzymes

Monoacylglycerol lipase is an enzyme that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.

<span class="mw-page-title-main">Diacylglycerol lipase</span> Enzyme that breaks down diacylglycerol in many organisms.

Diacylglycerol lipase, also known as DAG lipase, DAGL, or DGL, is an enzyme that catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid and monoacylglycerol:

diacylglycerol + H2O ⇌ monoacylglycerol + free fatty acid

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span>

Fatty-acid amide hydrolase 1 or FAAH-1(EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">2-Arachidonoylglycerol</span> Chemical compound

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

Serine hydrolases are one of the largest known enzyme classes comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A defining characteristic of these enzymes is the presence of a particular serine at the active site, which is used for the hydrolysis of substrates. The hydrolysis of the ester or peptide bond proceeds in two steps. First, the acyl part of the substrate is transferred to the serine, making a new ester or amide bond and releasing the other part of the substrate is released. Later, in a slower step, the bond between the serine and the acyl group is hydrolyzed by water or hydroxide ion, regenerating free enzyme. Unlike other, non-catalytic, serines, the reactive serine of these hydrolases is typically activated by a proton relay involving a catalytic triad consisting of the serine, an acidic residue and a basic residue, although variations on this mechanism exist.

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

<span class="mw-page-title-main">Methoxy arachidonyl fluorophosphonate</span> Chemical compound

Methoxy arachidonyl fluorophosphonate, commonly referred as MAFP, is an irreversible active site-directed enzyme inhibitor that inhibits nearly all serine hydrolases and serine proteases. It inhibits phospholipase A2 and fatty acid amide hydrolase with special potency, displaying IC50 values in the low-nanomolar range. In addition, it binds to the CB1 receptor in rat brain membrane preparations (IC50 = 20 nM), but does not appear to agonize or antagonize the receptor, though some related derivatives do show cannabinoid-like properties.

<span class="mw-page-title-main">RP1</span> Protein-coding gene in humans

Oxygen-regulated protein 1 also known as retinitis pigmentosa 1 protein (RP1) is a protein that in humans is encoded by the RP1 gene.

<span class="mw-page-title-main">JZL184</span> Chemical compound

JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG). It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.

<span class="mw-page-title-main">Lipase</span> Class of enzymes which cleave fats via hydrolysis

In biochemistry, lipase refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.

<span class="mw-page-title-main">Retinal degeneration (rhodopsin mutation)</span> Retinopathy

Retinal degeneration is a retinopathy which consists in the deterioration of the retina caused by the progressive death of its cells. There are several reasons for retinal degeneration, including artery or vein occlusion, diabetic retinopathy, R.L.F./R.O.P., or disease. These may present in many different ways such as impaired vision, night blindness, retinal detachment, light sensitivity, tunnel vision, and loss of peripheral vision to total loss of vision. Of the retinal degenerative diseases retinitis pigmentosa (RP) is a very important example.

<span class="mw-page-title-main">URB602</span> Chemical compound

URB602 is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003. A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG. However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.

<span class="mw-page-title-main">2-Oleoylglycerol</span> Chemical compound

2-Oleoylglycerol (2OG) is a monoacylglycerol that is found in biologic tissues. Its synthesis is derived from diacylglycerol precursors. It is metabolized to oleic acid and glycerol primarily by the enzyme monoacylglycerol lipase (MAGL). In 2011, 2OG was found to be an endogenous ligand to GPR119. 2OG has been shown to increase glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels following administration to the small intestine.

<span class="mw-page-title-main">JZL195</span> Chemical compound

JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively.

IDFP is an organophosphorus compound related to the nerve agent sarin.

<span class="mw-page-title-main">ABHD6</span> Protein-coding gene in the species Homo sapiens

alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.

An endocannabinoid enhancer (eCBE) is a type of cannabinoidergic drug that enhances the activity of the endocannabinoid system by increasing extracellular concentrations of endocannabinoids. Examples of different types of eCBEs include fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, and endocannabinoid transporter (eCBT) inhibitors. An example of an actual eCBE is AM404, the active metabolite of the analgesic paracetamol and a dual FAAH inhibitor and eCBRI.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000100997 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032046 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 Savinainen JR, Saario SM, Laitinen JT (February 2012). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors". Acta Physiologica. 204 (2): 267–76. doi:10.1111/j.1748-1716.2011.02280.x. PMC   3320662 . PMID   21418147.
  6. 1 2 3 4 Parkkari T, Haavikko R, Laitinen T, Navia-Paldanius D, Rytilahti R, Vaara M, et al. (2014). "Discovery of triterpenoids as reversible inhibitors of α/β-hydrolase domain containing 12 (ABHD12)". PLOS ONE. 9 (5): e98286. Bibcode:2014PLoSO...998286P. doi: 10.1371/journal.pone.0098286 . PMC   4045134 . PMID   24879289.
  7. 1 2 Blankman JL, Simon GM, Cravatt BF (December 2007). "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & Biology. 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC   2692834 . PMID   18096503.
  8. ↑ Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, et al. (August 2010). "The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors". Nature Neuroscience. 13 (8): 951–7. doi:10.1038/nn.2601. PMC   2970523 . PMID   20657592.
  9. 1 2 3 4 5 Navia-Paldanius D, Savinainen JR, Laitinen JT (November 2012). "Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)". Journal of Lipid Research. 53 (11): 2413–24. doi:10.1194/jlr.M030411. PMC   3466009 . PMID   22969151.
  10. 1 2 3 4 5 Fiskerstrand T, H'mida-Ben Brahim D, Johansson S, M'zahem A, Haukanes BI, Drouot N, et al. (September 2010). "Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism". American Journal of Human Genetics. 87 (3): 410–7. doi:10.1016/j.ajhg.2010.08.002. PMC   2933347 . PMID   20797687.
  11. 1 2 3 4 5 Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF (January 2013). "ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC". Proceedings of the National Academy of Sciences of the United States of America. 110 (4): 1500–5. Bibcode:2013PNAS..110.1500B. doi: 10.1073/pnas.1217121110 . PMC   3557017 . PMID   23297193.
  12. 1 2 Ayuso C, Garcia-Sandoval B, Najera C, Valverde D, Carballo M, Antiñolo G, et al. (Spanish Multicentric and Multidisciplinary Group for Research into Retinitis Pigmentosa) (1995). "Retinitis pigmentosa in Spain". Clinical Genetics. 48 (3): 120–122. doi:10.1111/j.1399-0004.1995.tb04069.x. S2CID   85403725.
  13. ↑ Ali MU, Rahman MS, Cao J, Yuan PX (August 2017). "Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario". 3 Biotech. 7 (4): 251. doi:10.1007/s13205-017-0878-3. PMC   5515732 . PMID   28721681.
  14. 1 2 3 Nishiguchi KM, Avila-Fernandez A, van Huet RA, Corton M, Pérez-Carro R, Martín-Garrido E, et al. (August 2014). "Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration". Ophthalmology. 121 (8): 1620–7. doi:10.1016/j.ophtha.2014.02.008. PMID   24697911.
  15. 1 2 3 Tingaud-Sequeira A, Raldúa D, Lavie J, Mathieu G, Bordier M, Knoll-Gellida A, et al. (February 2017). "Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC". Neurobiology of Disease. 98: 36–51. doi:10.1016/j.nbd.2016.11.008. PMID   27890673. S2CID   207070270.
  16. ↑ Eisenberger T, Slim R, Mansour A, Nauck M, Nürnberg G, Nürnberg P, et al. (September 2012). "Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3". Orphanet Journal of Rare Diseases. 7 (1): 59. doi: 10.1186/1750-1172-7-59 . PMC   3518140 . PMID   22938382.
  17. ↑ Chen DH, Naydenov A, Blankman JL, Mefford HC, Davis M, Sul Y, et al. (December 2013). "Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects". Human Mutation. 34 (12): 1672–8. doi:10.1002/humu.22437. PMC   3855015 . PMID   24027063.
  18. 1 2 Yoshimura H, Hashimoto T, Murata T, Fukushima K, Sugaya A, Nishio SY, et al. (May 2015). "Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness". The Annals of Otology, Rhinology, and Laryngology. 124 (1_suppl): 77S–83S. doi:10.1177/0003489415574513. PMID   25743180. S2CID   23734319.
  19. ↑ Frasquet M, Lupo V, Chumillas MJ, Vázquez-Costa JF, Espinós C, Sevilla T (April 2018). "Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene". Journal of the Neurological Sciences. 387: 134–138. doi:10.1016/j.jns.2018.02.021. PMID   29571850. S2CID   4234582.
  20. ↑ Kamat SS, Camara K, Parsons WH, Chen DH, Dix MM, Bird TD, et al. (February 2015). "Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay". Nature Chemical Biology. 11 (2): 164–71. doi:10.1038/nchembio.1721. PMC   4301979 . PMID   25580854.
  21. ↑ Schwenk J, Harmel N, Brechet A, Zolles G, Berkefeld H, Müller CS, et al. (May 2012). "High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes". Neuron. 74 (4): 621–33. doi: 10.1016/j.neuron.2012.03.034 . PMID   22632720.
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