Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)
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Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11). / Navia-Paldanius, Dina; Patel, Jayendra Z.; López Navarro, Miriam; Jakupović, Hermina; Goffart, Steffi; Pasonen-Seppänen, Sanna; Nevalainen, Tapio J.; Jääskeläinen, Tiina; Laitinen, Tuomo; Laitinen, Jarmo T.; Savinainen, Juha R.
In: European Journal of Pharmaceutical Sciences, Vol. 93, 10.10.2016, p. 253-263.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)
AU - Navia-Paldanius, Dina
AU - Patel, Jayendra Z.
AU - López Navarro, Miriam
AU - Jakupović, Hermina
AU - Goffart, Steffi
AU - Pasonen-Seppänen, Sanna
AU - Nevalainen, Tapio J.
AU - Jääskeläinen, Tiina
AU - Laitinen, Tuomo
AU - Laitinen, Jarmo T.
AU - Savinainen, Juha R.
PY - 2016/10/10
Y1 - 2016/10/10
N2 - ABHD11 (α/β-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.
AB - ABHD11 (α/β-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.
KW - ABHD11
KW - ABPP
KW - AFMID
KW - Homology modelling
KW - Inhibitor screening
KW - LYPLA2
KW - Serine hydrolases
UR - http://www.scopus.com/inward/record.url?scp=84984604676&partnerID=8YFLogxK
U2 - 10.1016/j.ejps.2016.08.031
DO - 10.1016/j.ejps.2016.08.031
M3 - Journal article
C2 - 27544863
AN - SCOPUS:84984604676
VL - 93
SP - 253
EP - 263
JO - Norvegica Pharmaceutica Acta
JF - Norvegica Pharmaceutica Acta
SN - 0928-0987
ER -
ID: 253189442