Currently fully validated human acyl-protein thioesterases are APT1[8] and APT2[9] which share 66% sequence homology.[10]Additionally there are a handful of putative acyl-protein thioesterases reported, including the ABHD17 enzyme family.[11][12] In the lysosome, PPT1 of the palmitoyl protein thioesterase family has similar enzymatic activity as acyl-protein thioesterases.
Structure
Active site, hydrophobic tunnel and lid-loop of acyl-protein thioesterases.
Acyl-protein thioesterases feature 3 major structural components that determine protein function and substrate processing: 1. A conserved, classical catalytic triad to break ester and thioester bonds;[2] 2. A long hydrophobic substrate tunnel to accommodate the palmitoyl moiety, as identified in the crystal structures of human acyl-protein thioesterase 1,[2] human acyl-protein thioesterase 2[13] and Zea mays acyl-protein thioesterase 2;[14] 3. A lid-loop that covers the catalytic site, is highly flexible and is a main factor determining the enzyme's product release rate.[14]
Mechanism of how acyl-protein thioesterases release their product by using a flexible lid-loop covering the substrate binding tunnel. Nature Communications8(1):2201, Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/
Inhibition
The involvement in controlling the localization of the oncogene Ras has made acyl-protein thioesterases potential cancerdrug targets.[15]Inhibition of acyl-protein thioesterases is believed to increase mislocalization of Ras at the cell's membranes, eventually leading to a collapse of the Ras cycle. Inhibitors for acyl-protein thioesterases have been specifically targeting the hydrophobic substrate tunnel,[16][13] the catalytic site serine[17] or both.[18]
Research
Current approaches to study the biological activity of Acyl-protein Thioesterases include proteomics, monitoring the trafficking of microinjected fluorescent substrates,[19][7] the use of cell-permeable substrate mimetics,[20] and cell permeable small molecule fluorescent chemical tools.[21][22][23][24]
^ a b cDevedjiev Y, Dauter Z, Kuznetsov SR, Jones TL, Derewenda ZS (November 2000). "Crystal structure of the human acyl protein thioesterase I from a single X-ray data set to 1.5 A". Structure. 8 (11): 1137–46. doi:10.1016/s0969-2126(00)00529-3. PMID 11080636.
^Wang A, Yang HC, Friedman P, Johnson CA, Dennis EA (February 1999). "A specific human lysophospholipase: cDNA cloning, tissue distribution and kinetic characterization". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1437 (2): 157–69. doi:10.1016/s1388-1981(99)00012-8. PMID 10064899.
^Tian L, McClafferty H, Knaus HG, Ruth P, Shipston MJ (April 2012). "Distinct acyl protein transferases and thioesterases control surface expression of calcium-activated potassium channels". The Journal of Biological Chemistry. 287 (18): 14718–25. doi:10.1074/jbc.M111.335547. PMC 3340283. PMID 22399288.
^Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (March 2005). "An acylation cycle regulates localization and activity of palmitoylated Ras isoforms". Science. 307 (5716): 1746–52. Bibcode:2005Sci...307.1746R. doi:10.1126/science.1105654. PMID 15705808. S2CID 12408991.
^ a bDekker FJ, Rocks O, Vartak N, Menninger S, Hedberg C, Balamurugan R, Wetzel S, Renner S, Gerauer M, Schölermann B, Rusch M, Kramer JW, Rauh D, Coates GW, Brunsveld L, Bastiaens PI, Waldmann H (June 2010). "Small-molecule inhibition of APT1 affects Ras localization and signaling". Nature Chemical Biology. 6 (6): 449–56. doi:10.1038/nchembio.362. PMID 20418879.
^Duncan JA, Gilman AG (June 1998). "A cytoplasmic acyl-protein thioesterase that removes palmitate from G protein alpha subunits and p21(RAS)". The Journal of Biological Chemistry. 273 (25): 15830–7. doi:10.1074/jbc.273.25.15830. PMID 9624183.
^Conibear E, Davis NG (December 2010). "Palmitoylation and depalmitoylation dynamics at a glance". Journal of Cell Science. 123 (Pt 23): 4007–10. doi:10.1242/jcs.059287. PMC 2987437. PMID 21084560.
^Lin DT, Conibear E (December 2015). "ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization". eLife. 4: e11306. doi:10.7554/eLife.11306. PMC 4755737. PMID 26701913.
^Long JZ, Cravatt BF (October 2011). "The metabolic serine hydrolases and their functions in mammalian physiology and disease". Chemical Reviews. 111 (10): 6022–63. doi:10.1021/cr200075y. PMC 3192302. PMID 21696217.
^ a bWon SJ, Davda D, Labby KJ, Hwang SY, Pricer R, Majmudar JD, Armacost KA, Rodriguez LA, Rodriguez CL, Chong FS, Torossian KA, Palakurthi J, Hur ES, Meagher JL, Brooks CL, Stuckey JA, Martin BR (December 2016). "Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2)". ACS Chemical Biology. 11 (12): 3374–3382. doi:10.1021/acschembio.6b00720. PMC 5359770. PMID 27748579.
^ a bBürger M, Willige BC, Chory J (December 2017). "A hydrophobic anchor mechanism defines a deacetylase family that suppresses host response against YopJ effectors". Nature Communications. 8 (1): 2201. Bibcode:2017NatCo...8.2201B. doi:10.1038/s41467-017-02347-w. PMC 5736716. PMID 29259199.
^Chavda B, Arnott JA, Planey SL (September 2014). "Targeting protein palmitoylation: selective inhibitors and implications in disease". Expert Opinion on Drug Discovery. 9 (9): 1005–19. doi:10.1517/17460441.2014.933802. PMID 24967607. S2CID 207494086.
^Rusch M, Zimmermann TJ, Bürger M, Dekker FJ, Görmer K, Triola G, Brockmeyer A, Janning P, Böttcher T, Sieber SA, Vetter IR, Hedberg C, Waldmann H (October 2011). "Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras-signaling modulators palmostatin B and M". Angewandte Chemie. 50 (42): 9838–42. doi:10.1002/anie.201102967. PMID 21905186.
^Zimmermann TJ, Bürger M, Tashiro E, Kondoh Y, Martinez NE, Görmer K, Rosin-Steiner S, Shimizu T, Ozaki S, Mikoshiba K, Watanabe N, Hall D, Vetter IR, Osada H, Hedberg C, Waldmann H (January 2013). "Boron-based inhibitors of acyl protein thioesterases 1 and 2". ChemBioChem. 14 (1): 115–22. doi:10.1002/cbic.201200571. PMID 23239555. S2CID 205557212.
^Görmer K, Bürger M, Kruijtzer JA, Vetter I, Vartak N, Brunsveld L, Bastiaens PI, Liskamp RM, Triola G, Waldmann H (May 2012). "Chemical-biological exploration of the limits of the Ras de- and repalmitoylating machinery". ChemBioChem. 13 (7): 1017–23. doi:10.1002/cbic.201200078. PMID 22488913. S2CID 37748152.
^Creaser SP, Peterson BR (March 2002). "Sensitive and rapid analysis of protein palmitoylation with a synthetic cell-permeable mimic of SRC oncoproteins". Journal of the American Chemical Society. 124 (11): 2444–5. doi:10.1021/ja017671x. PMID 11890786.
^Kathayat RS, Elvira PD, Dickinson BC (February 2017). "A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling". Nature Chemical Biology. 13 (2): 150–152. doi:10.1038/nchembio.2262. PMC 5247352. PMID 27992880.
^Qiu T, Kathayat RS, Cao Y, Beck MW, Dickinson BC (January 2018). "A Fluorescent Probe with Improved Water Solubility Permits the Analysis of Protein S-Depalmitoylation Activity in Live Cells". Biochemistry. 57 (2): 221–225. doi:10.1021/acs.biochem.7b00835. PMC 5823605. PMID 29023093.
^Beck MW, Kathayat RS, Cham CM, Chang EB, Dickinson BC (November 2017). "S-depalmitoylases in live cells and tissues". Chemical Science. 8 (11): 7588–7592. doi:10.1039/C7SC02805A. PMC 5848818. PMID 29568422.
^Kathayat RS, Cao Y, Elvira PD, Sandoz PA, Zaballa ME, Springer MZ, Drake LE, Macleod KF, van der Goot FG, Dickinson BC (January 2018). "Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes". Nature Communications. 9 (1): 334. Bibcode:2018NatCo...9..334K. doi:10.1038/s41467-017-02655-1. PMC 5780395. PMID 29362370.