ABHD10

ABHD10 is a serine hydrolase that operates as a protein S-depalmitoylase in the mitochondrial matrix, controlling mitochondrial redox homeostasis and lipid-related function across multiple tissues (PMID:31740833, PMID:41285782). Its catalytic mechanism rests on a serine nucleophile, established by covalent serine-directed inhibitors and activity-based protein profiling that classify it as an active serine hydrolase (PMID:22400490). In its depalmitoylase role, ABHD10 removes palmitoyl groups from peroxiredoxin-5 (PRDX5) at the active-site cysteine (Cys100), thereby preserving PRDX5 antioxidant capacity and limiting mitochondrial oxidative stress (PMID:31740833, PMID:37400491). In testis, ABHD10 is a mitochondrial matrix depalmitoylase essential for sperm mitochondrial sheath formation and male fertility, acting on substrates including SPATA19, GK2, PDHX, NDUFV1, and SDHB, with direct physical interactions demonstrated for SPATA19, GK2, and PDHX (PMID:41285782). Beyond its depalmitoylase activity, ABHD10 also functions in human liver as an acyl-glucuronide hydrolase, deglucuronidating mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide (PMID:22294686, PMID:25217485). ABHD10 expression is transcriptionally repressed by ELK-3 downstream of TGFβ1/EGF signaling, linking signaling-driven loss of ABHD10 to increased PRDX5 palmitoylation and hepatocyte oxidative damage (PMID:37400491).

1. 2012 High

   Established the first defined enzymatic function of ABHD10 by identifying it as the liver enzyme that hydrolyzes mycophenolic acid acyl-glucuronide, resolving which protein clears this reactive metabolite.

   Evidence Purification from human liver cytosol, sequence confirmation, and recombinant expression in Sf9 cells with kinetic and chemical inhibition profiling

   PMID:22294686

   Open questions at the time

   • Did not define catalytic residues or structure
   • Did not address whether deglucuronidation is the physiological role versus an in vitro activity
2. 2012 Medium

   Confirmed ABHD10 is a bona fide serine hydrolase and provided a selective covalent inhibitor, supplying chemical tools to interrogate its activity in cells.

   Evidence Competitive activity-based protein profiling and aza-β-lactam (ABL303) covalent inactivation in vitro and in living cells

   PMID:22400490

   Open questions at the time

   • Did not identify endogenous substrates
   • Single lab
3. 2014 Medium

   Extended ABHD10's acyl-glucuronide hydrolase role to a second substrate class, showing it, rather than carboxylesterases, deglucuronidates probenecid acyl-glucuronide.

   Evidence Recombinant enzyme assay and chemical inhibition comparison against human liver homogenates

   PMID:25217485

   Open questions at the time

   • Did not establish in vivo relevance
   • Single lab; relied on inhibition-profile matching rather than genetic knockout
4. 2014 Low

   Independently corroborated ABHD10 as an active serine hydrolase using a distinct inhibitor chemotype in intact cells.

   Evidence Rocaglate-derived β-lactone inhibition by ABPP in vitro and in PC3 cells

   PMID:24447064

   Open questions at the time

   • Single ABPP readout with no mechanistic follow-up specific to ABHD10 function
   • No substrate or pathway link
5. 2019 High

   Reframed ABHD10 as a protein S-depalmitoylase by identifying PRDX5 active-site cysteine palmitoylation as a regulated substrate, connecting the enzyme to mitochondrial redox control.

   Evidence Mitochondrial-targeted depalmitoylase inhibition and PRDX5 substrate identification with active-site cysteine readout

   PMID:31740833

   Open questions at the time

   • Did not enumerate the full substrate repertoire
   • Did not resolve how ABHD10 is targeted to specific palmitoylated cysteines
6. 2023 Medium

   Placed ABHD10 within a signaling axis by showing ELK-3 directly represses its promoter downstream of TGFβ1/EGF, linking ABHD10 loss to PRDX5 Cys100 palmitoylation and liver injury.

   Evidence Promoter binding assays, site-specific palmitoylation readout, and Abhd10 overexpression rescue in an alcoholic liver disease mouse model

   PMID:37400491

   Open questions at the time

   • Did not define upstream signaling kinetics of ELK-3 activation
   • Single lab
7. 2025 High

   Defined an essential in vivo role for ABHD10 in spermatogenesis, identifying it as a testis mitochondrial matrix depalmitoylase acting on multiple sheath and metabolic substrates.

   Evidence Knock-in and knockout mice, super-resolution and electron microscopy, mitochondrial acyl-biotin exchange mass spectrometry, co-immunoprecipitation, and proximity labeling

   PMID:41285782

   Open questions at the time

   • Mechanism by which substrate hyper-palmitoylation disrupts sheath assembly not fully resolved
   • Relative contribution of each substrate to the fertility phenotype unclear
8. 2026 Medium

   Implicated ABHD10 in cellular senescence and mitochondrial lipid handling through a new interactor, broadening its functional context beyond redox and fertility.

   Evidence Co-immunoprecipitation of ABHD10–KCMF1 and ABHD10 silencing in HEI-OC1 cells with senescence, ROS, membrane potential, and lipid readouts

   PMID:42206676

   Open questions at the time

   • Functional significance and directionality of the KCMF1 complex not defined
   • Single lab; correlative cellular readouts

• How a single mitochondrial matrix serine hydrolase reconciles distinct activities (protein S-depalmitoylation versus acyl-glucuronide hydrolysis) and selects substrates across tissues remains unresolved.
• No structural model of substrate or active-site recognition in the corpus
• Mechanism of substrate selectivity across tissues unknown
• Relationship between its cytosolic/liver glucuronide activity and matrix depalmitoylase activity not integrated