ABHD2 (Abhydrolase domain-containing protein 2) is an integral membrane serine hydrolase belonging to the alpha/beta hydrolase superfamily. It functions as a monoacylglycerol lipase that hydrolyzes 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG) to glycerol and arachidonic acid, as well as displaying triacylglycerol lipase and ester hydrolase activities against short- and long-chain ester substrates. The catalytic triad consists of Ser207, Asp345, and His376. ABHD2 is anchored to membranes via an N-terminal transmembrane domain (type II orientation). In human sperm, ABHD2 localizes to the flagellum and plasma membrane where it plays a key role in sperm capacitation: progesterone activates ABHD2 lipase activity, leading to depletion of the endocannabinoid 2-AG from the membrane, which relieves 2-AG-mediated inhibition of the CatSper calcium channel and permits calcium influx required for sperm activation. However, whether progesterone directly binds ABHD2 or acts through an indirect mechanism remains debated. In somatic cells, ABHD2 has been localized to the endoplasmic reticulum where it may regulate calcium release. Mouse knockout studies also implicate ABHD2 in hepatic phospholipid and cardiolipin metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043401 steroid hormone receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for involvement in steroid hormone receptor signaling pathway. ABHD2 is proposed to mediate non-genomic progesterone signaling in sperm, where progesterone activates ABHD2 lipase activity to regulate CatSper channel opening [PMID:26989199]. This is a non-genomic steroid signaling pathway rather than a classical nuclear receptor pathway. Reason: ABHD2 functions in a progesterone-dependent signaling cascade in sperm. The IBA annotation at the level of "steroid hormone receptor signaling pathway" is appropriate as it captures the progesterone-responsive role without being overly specific about the mechanism (which remains debated). Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane file:human/ABHD2/ABHD2-deep-research-falcon.md ABHD2 is proposed to function as (or within) this membrane progesterone-sensing machinery by hydrolyzing 2-AG |
| GO:0008126 acetylesterase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for acetylesterase activity. Recombinant ABHD2 was shown to hydrolyze p-nitrophenyl acetate with Km of 12.40 mM [PMID:27247428], directly demonstrating acetylesterase activity. Reason: Acetylesterase activity is experimentally validated for ABHD2 by direct enzymatic assay with pNP acetate substrate. The IBA annotation is consistent with the experimental data from PMID:27247428. Supporting Evidence: PMID:27247428 ABHD2 cleaved, pNPA with a Km of 12.40Β±1.02 mM, Vmax of 2.69Β±0.15 ΞΌmol/sΒ·mg |
| GO:0047372 monoacylglycerol lipase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for monoacylglycerol lipase activity. This is the best-characterized core enzymatic function of ABHD2. Miller et al. (2016) demonstrated that ABHD2 hydrolyzes 2-arachidonoylglycerol and 1-arachidonoylglycerol, producing glycerol and arachidonic acid [PMID:26989199]. Reason: Monoacylglycerol lipase activity is the primary physiologically relevant enzymatic function of ABHD2. The hydrolysis of 2-AG by ABHD2 is central to its role in sperm activation and CatSper channel regulation. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0036126 sperm flagellum | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for localization to sperm flagellum. Immunostaining in the Miller et al. (2016) study showed ABHD2 localized to the human sperm flagellum [PMID:26989199], consistent with proximity to the flagellar CatSper channel. Reason: Sperm flagellum localization is directly supported by immunostaining data and is consistent with ABHD2's functional role in regulating the flagellar CatSper channel during sperm activation. Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase file:human/ABHD2/ABHD2-deep-research-falcon.md Immunostaining shows ABHD2 localized to the human sperm flagellum, consistent with proximity to the flagellar CatSper channel |
| GO:0046464 acylglycerol catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for involvement in acylglycerol catabolic process. ABHD2 hydrolyzes 2-arachidonoylglycerol and triacylglycerols [PMID:26989199, PMID:27247428], directly contributing to acylglycerol catabolism. Reason: ABHD2 catalyzes the hydrolysis of both monoacylglycerols (2-AG) and triacylglycerols, making acylglycerol catabolic process an appropriate biological process annotation that accurately reflects the enzyme's function. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane PMID:27247428 His-tag purified protein showed TAG lipase activity |
| GO:0048240 sperm capacitation | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for involvement in sperm capacitation. The Miller et al. (2016) study demonstrated that ABHD2-mediated depletion of 2-AG in response to progesterone leads to CatSper activation and calcium influx required for sperm activation [PMID:26989199]. Reason: Sperm capacitation is the primary biological context in which ABHD2 function has been characterized. The progesterone-ABHD2-2AG-CatSper axis is the dominant functional model for ABHD2 in reproductive biology. Supporting Evidence: PMID:26989199 its removal leads to calcium influx via CatSper and ensures sperm activation |
| GO:0051792 medium-chain fatty acid biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for involvement in medium-chain fatty acid biosynthetic process. This annotation appears to be derived from phylogenetic inference based on yeast orthologs (SGD references in the WITH/FROM column). While ABHD2 does have ester hydrolase activity against medium-chain substrates like pNP butyrate [PMID:27247428], the primary substrates of ABHD2 are long-chain arachidonoylglycerols and triacylglycerols, not medium-chain fatty acids. Reason: The annotation is based on phylogenetic inference from yeast orthologs. While ABHD2 can hydrolyze medium-chain ester substrates in vitro, its primary physiological substrates are long-chain acylglycerols (2-AG, TAG). Medium-chain fatty acid biosynthesis is not a well-established function of ABHD2 in human cells. Supporting Evidence: PMID:27247428 ABHD2 cleaved, pNPA with a Km of 12.40Β±1.02 mM, Vmax of 2.69Β±0.15 ΞΌmol/sΒ·mg and kcat/Km of 11.23Β±1.22 Mβ1Β·sβ1, pNPB with a Km of 11.76Β±1.15 mM |
| GO:0051793 medium-chain fatty acid catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for involvement in medium-chain fatty acid catabolic process. Similar to the biosynthetic process annotation, this is derived from phylogenetic inference via yeast orthologs. ABHD2 can cleave medium-chain ester substrates in vitro but its primary physiological role involves long-chain arachidonoylglycerol hydrolysis. Reason: Same rationale as for GO:0051792 above. The in vitro activity against medium-chain substrates is documented but the primary physiological function of ABHD2 involves long-chain substrates. This is not a core function. Supporting Evidence: PMID:27247428 the present study highlights the TAG lipase activity of ABHD2 along with both long and short chain esterase activities against pNP palmitate, butyrate and acetate substrates respectively |
| GO:0097524 sperm plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for localization to sperm plasma membrane. ABHD2 is a type II membrane protein with an N-terminal transmembrane anchor, and has been localized to the sperm flagellum membrane by immunostaining [PMID:26989199]. UniProt annotates it as a single-pass type II membrane protein in the cell/flagellum membrane. Reason: Sperm plasma membrane localization is consistent with ABHD2's predicted type II membrane topology and its functional role in hydrolyzing membrane-associated 2-AG at the sperm surface. Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0030518 nuclear receptor-mediated steroid hormone signaling pathway | IEA GO_REF:0000108 | REMOVE | Summary: IEA annotation inferred from the IDA annotation of GO:0003707 (nuclear steroid receptor activity) via logical inter-ontology link. This is problematic because ABHD2 does not function as a nuclear steroid receptor. It is a membrane-bound lipase that responds to progesterone via a non-genomic mechanism. The nuclear receptor annotation (GO:0003707) from which this was derived is itself questionable. Reason: ABHD2 mediates non-genomic progesterone signaling at the cell membrane, not nuclear receptor-mediated signaling. It is a serine hydrolase/lipase, not a nuclear receptor. This IEA annotation was propagated from an incorrect IDA annotation of nuclear steroid receptor activity. The parent GO:0043401 (steroid hormone receptor signaling pathway) annotation is more appropriate. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane file:human/ABHD2/ABHD2-deep-research-falcon.md ABHD2 is proposed to function as (or within) this membrane progesterone-sensing machinery by hydrolyzing 2-AG |
| GO:0004806 triacylglycerol lipase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA annotation based on Rhea mapping from the UniProt catalytic activity annotation (EC 3.1.1.79). Kumar et al. (2016) directly demonstrated TAG lipase activity for recombinant ABHD2 with activity of 1.14 +/- 0.11 umol/s/mg [PMID:27247428]. Reason: Triacylglycerol lipase activity is experimentally validated for ABHD2 by direct enzymatic assay. The IEA mapping is correct and supported by primary experimental evidence. Supporting Evidence: PMID:27247428 This affinity purified recombinant hABHD2 protein fraction showed TAG lipase activity of 1.14Β±0.11 ΞΌmol/sΒ·mg of protein against controls |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location mapping. ABHD2 is annotated in UniProt as a cell membrane protein with a single-pass type II transmembrane domain. More specific sperm plasma membrane (GO:0097524) and sperm flagellum (GO:0036126) annotations exist. Reason: Plasma membrane localization is correct for ABHD2, which is a type II single-pass membrane protein. This broader annotation is acceptable alongside the more specific sperm-related CC annotations, as ABHD2 is expressed in multiple tissues (not just sperm). Supporting Evidence: file:human/ABHD2/ABHD2-deep-research-falcon.md ABHD2 is an integral membrane serine hydrolase with an N-terminal transmembrane anchor |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping (KW-0443 Lipid metabolism). ABHD2 is a lipase that hydrolyzes acylglycerols and triacylglycerols, so involvement in lipid metabolism is correct but very broad. Reason: While this is a broad term, it is not incorrect. More specific annotations exist for acylglycerol catabolic process (GO:0046464). The broader annotation is acceptable as it captures the general functional category. |
| GO:0008126 acetylesterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for acetylesterase activity via combined automated methods (Rhea/EC mapping). This is a duplicate of the IBA and IDA annotations for the same term and is experimentally supported by PMID:27247428. Reason: Consistent with both the IBA annotation and the direct experimental evidence from PMID:27247428 showing ABHD2 cleaves pNP acetate. Supporting Evidence: PMID:27247428 ABHD2 cleaved, pNPA with a Km of 12.40Β±1.02 mM, Vmax of 2.69Β±0.15 ΞΌmol/sΒ·mg |
| GO:0016042 lipid catabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping (KW-0442 Lipid degradation). ABHD2 catalyzes the hydrolytic degradation of acylglycerols and triacylglycerols, which is lipid catabolism. Reason: Lipid catabolic process is correct and consistent with ABHD2's enzymatic function as a lipase. The more specific term acylglycerol catabolic process (GO:0046464) is also annotated. This broader annotation is acceptable. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping (KW-0378 Hydrolase). ABHD2 is an alpha/beta hydrolase with demonstrated lipase and esterase activities. Reason: Hydrolase activity is correct but very broad. More specific MF annotations exist (monoacylglycerol lipase activity, acetylesterase activity, triacylglycerol lipase activity). This broad parent annotation is acceptable as it is not incorrect. |
| GO:0047372 monoacylglycerol lipase activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA annotation based on EC number mapping (EC:3.1.1.23). This is a duplicate of the IBA and IDA annotations and is the core enzymatic function of ABHD2. Reason: Consistent with both IBA and IDA annotations and directly supported by experimental evidence showing ABHD2 hydrolyzes 2-arachidonoylglycerol. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0052689 carboxylic ester hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping (KW-0719 Serine esterase). ABHD2 hydrolyzes carboxylic esters including pNP acetate, butyrate, and palmitate [PMID:27247428]. Reason: Carboxylic ester hydrolase activity is correct and consistent with ABHD2's demonstrated esterase activities. This is a broader parent of acetylesterase activity and is acceptable. Supporting Evidence: PMID:27247428 the present study highlights the TAG lipase activity of ABHD2 along with both long and short chain esterase activities against pNP palmitate, butyrate and acetate substrates respectively |
| GO:0001669 acrosomal vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation transferred from mouse ortholog (UniProtKB:Q9QXM0) via Ensembl Compara. Acrosomal localization has been reported for mouse ABHD2 but direct evidence for human ABHD2 acrosomal localization is limited. The primary human localization data shows flagellar and plasma membrane localization [PMID:26989199]. Reason: This annotation is based on ortholog transfer from mouse. While plausible given the sperm context, the direct experimental evidence in human shows flagellar/plasma membrane localization rather than specific acrosomal localization. Keeping as non-core since it may reflect a species difference or additional localization not yet confirmed in human. |
| GO:0007340 acrosome reaction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation transferred from mouse ortholog via Ensembl Compara. While ABHD2 is involved in sperm capacitation which precedes the acrosome reaction, direct involvement of ABHD2 in the acrosome reaction itself has not been specifically demonstrated in human. Reason: The annotation is based on ortholog transfer from mouse. ABHD2 is involved in sperm capacitation and calcium signaling through CatSper, which can influence the acrosome reaction. However, the direct role in acrosome reaction is not well established for human ABHD2 specifically, so this is kept as non-core. |
| GO:0008126 acetylesterase activity | IDA PMID:27247428 Molecular characterization of human ABHD2 as TAG lipase and ... | ACCEPT | Summary: IDA annotation based on direct enzymatic assay. Kumar et al. (2016) demonstrated that purified recombinant ABHD2 cleaves p-nitrophenyl acetate with Km 12.40 mM and Vmax 2.69 umol/s/mg [PMID:27247428]. Reason: Directly supported by enzymatic kinetics data from recombinant ABHD2 protein assayed with pNP acetate substrate. The evidence is clear and well-quantified. Supporting Evidence: PMID:27247428 ABHD2 cleaved, pNPA with a Km of 12.40Β±1.02 mM, Vmax of 2.69Β±0.15 ΞΌmol/sΒ·mg and kcat/Km of 11.23Β±1.22 Mβ1Β·sβ1 |
| GO:0120516 diacylglycerol lipase activity | IDA PMID:27247428 Molecular characterization of human ABHD2 as TAG lipase and ... | UNDECIDED | Summary: IDA annotation for diacylglycerol lipase activity based on PMID:27247428. However, the Kumar et al. (2016) study demonstrated TAG lipase and ester hydrolase activities but did not specifically test diacylglycerol as a substrate. The TAG lipase assay measures hydrolysis of triacylglycerol to diacylglycerol (which would be an intermediate), but the primary activity demonstrated was TAG lipase activity. Reason: The PMID:27247428 study demonstrated TAG lipase activity (hydrolysis of triacylglycerol) and ester hydrolase activity against pNP substrates. Diacylglycerol lipase activity was not specifically assayed. TAG lipase activity could produce DAG as an intermediate, but this does not constitute direct evidence for DAG lipase activity. The annotation may be an over-interpretation of the TAG lipase data. Further evidence would be needed to confirm this specific activity. Supporting Evidence: PMID:27247428 This affinity purified recombinant hABHD2 protein fraction showed TAG lipase activity of 1.14Β±0.11 ΞΌmol/sΒ·mg of protein against controls |
| GO:0003707 nuclear steroid receptor activity | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | REMOVE | Summary: IDA annotation for nuclear steroid receptor activity based on the Miller et al. (2016) study. This is a problematic annotation. ABHD2 is not a nuclear receptor. It is a membrane-bound serine hydrolase that responds to progesterone, but it does so via a non-genomic mechanism at the plasma membrane, not through nuclear receptor-mediated transcription. The term "nuclear steroid receptor activity" implies nuclear localization and transcriptional regulation, which does not apply to ABHD2. Reason: ABHD2 is a membrane-anchored serine hydrolase that mediates non-genomic progesterone signaling. It is not a nuclear receptor and does not function in transcriptional regulation. The Miller et al. (2016) paper describes ABHD2 as a non-genomic progesterone receptor on sperm, explicitly contrasting it with nuclear receptor mechanisms. Recent work also questions whether progesterone directly binds ABHD2. This annotation is incorrect and should be removed. The response to progesterone (GO:0032570) and steroid hormone receptor signaling pathway (GO:0043401) annotations better capture the progesterone-responsive function. Supporting Evidence: PMID:26989199 Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway file:human/ABHD2/ABHD2-deep-research-falcon.md more recent biochemical/cell-based work indicates progesterone may not directly bind ABHD2 |
| GO:0032570 response to progesterone | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for involvement in response to progesterone. Miller et al. (2016) demonstrated that progesterone activates ABHD2 lipase activity, leading to 2-AG depletion and CatSper activation in sperm [PMID:26989199]. UniProt describes ABHD2 as a "progesterone-sensitive lipase." Reason: Response to progesterone is a well-supported annotation. The Miller et al. (2016) study demonstrated progesterone-dependent activation of ABHD2 lipase activity and downstream effects on CatSper channel regulation in sperm. Whether progesterone acts directly on ABHD2 or through an intermediary, the biological response to progesterone is clear. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0036126 sperm flagellum | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for localization to sperm flagellum based on immunostaining data from Miller et al. (2016) [PMID:26989199]. This is directly supported by microscopy evidence. Reason: Sperm flagellum localization is directly demonstrated by immunostaining in the Miller et al. (2016) study. This is consistent with ABHD2's functional role in regulating the flagellar CatSper calcium channel. Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa file:human/ABHD2/ABHD2-deep-research-falcon.md Immunostaining shows ABHD2 localized to the human sperm flagellum, consistent with proximity to the flagellar CatSper channel |
| GO:0042562 hormone binding | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | UNDECIDED | Summary: IDA annotation for hormone binding based on Miller et al. (2016), which used a photoaffinity progesterone probe to identify ABHD2 as a progesterone-binding protein in sperm [PMID:26989199]. However, more recent work from Arnolds et al. (2025) did not find progesterone effect on purified ABHD2 activity and questions direct binding. Reason: The original Miller et al. (2016) study identified ABHD2 via a progesterone photoaffinity probe, suggesting direct binding. However, more recent work questions whether progesterone directly binds ABHD2 or acts through an indirect mechanism. The evidence is conflicting and the annotation may need to be revisited once the mechanism is clarified. Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa, binds progesterone file:human/ABHD2/ABHD2-deep-research-falcon.md more recent biochemical/cell-based work indicates progesterone may not directly bind ABHD2 and that ABHD2 inhibition may not block progesterone-induced Ca2+ influx |
| GO:0043401 steroid hormone receptor signaling pathway | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for involvement in steroid hormone receptor signaling pathway from Miller et al. (2016). ABHD2 mediates progesterone-dependent signaling in sperm by hydrolyzing 2-AG to relieve CatSper inhibition [PMID:26989199]. Reason: ABHD2 functions in a progesterone-responsive signaling pathway in sperm. The term "steroid hormone receptor signaling pathway" is appropriate at this level of specificity, as it captures the non-genomic progesterone response without incorrectly implying a nuclear receptor mechanism. Supporting Evidence: PMID:26989199 Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone |
| GO:0046464 acylglycerol catabolic process | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for involvement in acylglycerol catabolic process based on Miller et al. (2016). The study demonstrated that ABHD2 hydrolyzes 2-arachidonoylglycerol to glycerol and arachidonic acid [PMID:26989199]. Reason: Directly supported by experimental evidence showing ABHD2 catalyzes the hydrolysis (catabolism) of the acylglycerol 2-AG. This is a core biological process for ABHD2. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0047372 monoacylglycerol lipase activity | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for monoacylglycerol lipase activity from Miller et al. (2016). The study demonstrated that recombinant ABHD2 hydrolyzes 2-arachidonoylglycerol (a monoacylglycerol) in a progesterone-enhanced manner [PMID:26989199]. Reason: This is the core enzymatic function of ABHD2, directly demonstrated by the Miller et al. (2016) study showing hydrolysis of 2-AG to glycerol and arachidonic acid. Supporting Evidence: PMID:26989199 acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0048240 sperm capacitation | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for involvement in sperm capacitation based on Miller et al. (2016). The study demonstrated that ABHD2-mediated 2-AG depletion leads to CatSper activation, calcium influx, and sperm activation [PMID:26989199]. Reason: Sperm capacitation is a core biological process for ABHD2. The progesterone-ABHD2-2AG- CatSper axis is a well-characterized pathway leading to sperm activation. The IDA evidence is based on electrophysiology, lipidomics, and antibody/inhibitor perturbation experiments. Supporting Evidence: PMID:26989199 its removal leads to calcium influx via CatSper and ensures sperm activation |
| GO:0097524 sperm plasma membrane | IDA PMID:26989199 Unconventional endocannabinoid signaling governs sperm activ... | ACCEPT | Summary: IDA annotation for localization to sperm plasma membrane based on Miller et al. (2016). ABHD2 is a type II membrane protein localized to the sperm flagellum membrane where it hydrolyzes 2-AG at the membrane surface [PMID:26989199]. Reason: Sperm plasma membrane localization is directly supported by immunostaining data and is consistent with ABHD2's function as a membrane-bound lipase acting on plasma membrane-associated 2-AG. Supporting Evidence: PMID:26989199 ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2-arachidonoylglycerol (2AG) from plasma membrane |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:28684316 Regulation of calcium release from the endoplasmic reticulum... | NEW | Summary: ABHD2 has been experimentally localized to the endoplasmic reticulum membrane in somatic cells (fibroblast-like cells), where ABHD2 knockdown attenuated ER calcium release and downstream mitochondrial calcium uptake. This represents a distinct localization from the sperm flagellum/plasma membrane context. Reason: Yun et al. (2017) [PMID:28684316] demonstrated ER membrane localization of ABHD2 in somatic cells using localization experiments. This represents an additional subcellular compartment where ABHD2 functions, beyond the sperm flagellum. This annotation is not currently in the GOA set but is supported by experimental evidence. Supporting Evidence: file:human/ABHD2/ABHD2-deep-research-falcon.md ABHD2 has been experimentally localized to the endoplasmic reticulum (ER) membrane (in fibroblast-like cells), where ABHD2 knockdown attenuated ER Ca2+ release and downstream mitochondrial Ca2+ uptake/cell death |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does progesterone directly bind ABHD2, or does it act through an intermediary mechanism to activate ABHD2 lipase activity? Recent work (Arnolds et al. 2025) questions the direct binding model proposed by Miller et al. (2016).
Suggested experts: Polina V. Lishko, Opher Gileadi
Q: What are the physiological substrates of ABHD2 in non-sperm tissues, particularly in the liver where Abhd2 knockout mice show altered phospholipid and cardiolipin composition?
Suggested experts: Alan D. Attie, Christina C. Leslie
Experiment: Use purified recombinant ABHD2 with biophysical binding assays (SPR, ITC, or thermal shift assays) to determine whether progesterone directly binds ABHD2 with physiologically relevant affinity. Include catalytically dead S207A mutant to distinguish binding from catalysis.
Hypothesis: ABHD2 directly binds progesterone via a specific binding site on its extracellular domain.
Experiment: Test purified ABHD2 against phosphatidylcholine and cardiolipin substrates in vitro to determine whether ABHD2 has direct phospholipase activity, as suggested by the mouse knockout lipidomic data from Price et al. (2023).
Hypothesis: ABHD2 has phospholipase activity against phosphatidylcholine and/or cardiolipin substrates.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)