Ngo N

References (5)

Title : Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron - Keller_2023_Nat.Chem.Biol__
Author(s) : Keller LJ , Nguyen TH , Liu LJ , Hurysz BM , Lakemeyer M , Guerra M , Gelsinger DJ , Chanin R , Ngo N , Lum KM , Faucher F , Ipock P , Niphakis MJ , Bhatt AS , O'Donoghue AJ , Huang KC , Bogyo M
Ref : Nat Chemical Biology , : , 2023
Abstract : Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.
ESTHER : Keller_2023_Nat.Chem.Biol__
PubMedSearch : Keller_2023_Nat.Chem.Biol__
PubMedID: 37349583

Title : ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth - Remsberg_2021_Nat.Chem.Biol__
Author(s) : Remsberg JR , Suciu RM , Zambetti NA , Hanigan TW , Firestone AJ , Inguva A , Long A , Ngo N , Lum KM , Henry CL , Richardson SK , Predovic M , Huang B , Dix MM , Howell AR , Niphakis MJ , Shannon K , Cravatt BF
Ref : Nat Chemical Biology , : , 2021
Abstract : Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.
ESTHER : Remsberg_2021_Nat.Chem.Biol__
PubMedSearch : Remsberg_2021_Nat.Chem.Biol__
PubMedID: 33927411
Gene_locus related to this paper: human-ABHD17A , human-ABHD17B , human-ABHD17C

Title : AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice - Erikci_2020_J.Biol.Chem_295_5891
Author(s) : Erikci Ertunc M , Kok BP , Parsons WH , Wang JG , Tan D , Donaldson CJ , Pinto AFM , Vaughan JM , Ngo N , Lum KM , Henry CL , Coppola AR , Niphakis MJ , Cravatt BF , Saez E , Saghatelian A
Ref : Journal of Biological Chemistry , 295 :5891 , 2020
Abstract : Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS-based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9(th) carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease.
ESTHER : Erikci_2020_J.Biol.Chem_295_5891
PubMedSearch : Erikci_2020_J.Biol.Chem_295_5891
PubMedID: 32152231

Title : Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator - Mizrak_2020_Cell.Rep_31_107805
Author(s) : Mizrak D , Bayin NS , Yuan J , Liu Z , Suciu RM , Niphakis MJ , Ngo N , Lum KM , Cravatt BF , Joyner AL , Sims PA
Ref : Cell Rep , 31 :107805 , 2020
Abstract : In the adult ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) generate new olfactory bulb (OB) neurons and glia throughout life. To map adult neuronal lineage progression, we profiled >56,000 V-SVZ and OB cells by single-cell RNA sequencing (scRNA-seq). Our analyses reveal the molecular diversity of OB neurons, including fate-mapped neurons, lineage progression dynamics, and an NSC intermediate enriched for Notum, which encodes a secreted WNT antagonist. SCOPE-seq technology, which links live-cell imaging with scRNA-seq, uncovers cell-size transitions during NSC differentiation and preferential NOTUM binding to proliferating neuronal precursors. Consistently, application of NOTUM protein in slice cultures and pharmacological inhibition of NOTUM in slice cultures and in vivo demonstrated that NOTUM negatively regulates V-SVZ proliferation. Timely, context-dependent neurogenesis demands adaptive signaling among neighboring progenitors. Our findings highlight a critical regulatory state during NSC activation marked by NOTUM, which attenuates WNT-stimulated proliferation in NSC progeny.
ESTHER : Mizrak_2020_Cell.Rep_31_107805
PubMedSearch : Mizrak_2020_Cell.Rep_31_107805
PubMedID: 32579931
Gene_locus related to this paper: human-NOTUM

Title : Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators - Clapper_2018_J.Pharmacol.Exp.Ther_367_494
Author(s) : Clapper JR , Henry CL , Niphakis MJ , Knize AM , Coppola AR , Simon GM , Ngo N , Herbst RA , Herbst DM , Reed AW , Cisar JS , Weber OD , Viader A , Alexander JP , Cunningham ML , Jones TK , Fraser IP , Grice CA , Ezekowitz RAB , O'Neill GP , Blankman JL
Ref : Journal of Pharmacology & Experimental Therapeutics , 367 :494 , 2018
Abstract : Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED(50) values of 1-2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders.
ESTHER : Clapper_2018_J.Pharmacol.Exp.Ther_367_494
PubMedSearch : Clapper_2018_J.Pharmacol.Exp.Ther_367_494
PubMedID: 30305428