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The Role of Hydrolases in Biology and Xenobiotics Metabolism
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The Role of Hydrolases in Biology and Xenobiotics Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 45858

Special Issue Editor

Dr. Christophe Morisseau

E-Mail Website
Guest Editor
Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, CA 95616, USA
Interests: epoxide hydrolase; oxylipin; enzyme inhibition; inflammation; neuropathic pain; metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chemical exposure can profoundly affect our health. Some exposures are voluntary (food, drugs), and some involuntary (environmental contaminants). Nevertheless, the metabolism of these chemicals is essential for their detoxification, elimination, and sometimes, their activation. Of the numerous enzymes involved in the metabolism of xenobiotics, this Special Issue will concentrate on hydrolases.

Hydrolases are part of a heterogeneous group of enzymes that catalyze bond cleavages by reactions with water. Beside some well documented roles in the metabolism of foreign chemicals, recent new findings demonstrate biological roles for hydrolases, implicating them in the regulation of cardiovascular diseases, inflammatory responses, and neurologic diseases among others.

This Special Issue will focus on both basic science and translational research of the biological roles of hydrolases in mammals, and also in their role in the metabolism of toxins and natural products.

Dr. Christophe Morisseau
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hydrolase
  • carboxylesterase
  • cholinesterase
  • endopeptidase
  • sulfatase
  • phosphatase
  • glucuronidase
  • epoxide hydrolase
  • oxylipin
  • inflammation
  • pain
  • cardio-vascular diseases
  • neuroinflammation

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

4 pages, 489 KiB  
Editorial
The Role of Hydrolases in Biology and Xenobiotics Metabolism
by Christophe Morisseau
Int. J. Mol. Sci. 2022, 23(9), 4870; https://doi.org/10.3390/ijms23094870 - 28 Apr 2022
Cited by 5 | Viewed by 1862
Abstract
Chemical exposure can profoundly affect our health, some being voluntary (food and drugs) and some involuntary (environmental contaminants) [...] Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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Research

Jump to: Editorial, Review

22 pages, 3012 KiB  
Article
Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates
by Magdalena Chrabąszczewska, Maria Winiewska-Szajewska, Natalia Ostrowska, Elżbieta Bojarska, Janusz Stępiński, Łukasz Mancewicz, Maciej Łukaszewicz, Joanna Trylska, Michał Taube, Maciej Kozak, Edward Darżynkiewicz and Renata Grzela
Int. J. Mol. Sci. 2021, 22(20), 10929; https://doi.org/10.3390/ijms222010929 - 10 Oct 2021
Cited by 6 | Viewed by 1992
Abstract
Nudt16 is a member of the NUDIX family of hydrolases that show specificity towards substrates consisting of a nucleoside diphosphate linked to another moiety X. Several substrates for hNudt16 and various possible biological functions have been reported. However, some of these reports contradict [...] Read more.
Nudt16 is a member of the NUDIX family of hydrolases that show specificity towards substrates consisting of a nucleoside diphosphate linked to another moiety X. Several substrates for hNudt16 and various possible biological functions have been reported. However, some of these reports contradict each other and studies comparing the substrate specificity of the hNudt16 protein are limited. Therefore, we quantitatively compared the affinity of hNudt16 towards a set of previously published substrates, as well as identified novel potential substrates. Here, we show that hNudt16 has the highest affinity towards IDP and GppG, with Kd below 100 nM. Other tested ligands exhibited a weaker affinity of several orders of magnitude. Among the investigated compounds, only IDP, GppG, m7GppG, AppA, dpCoA, and NADH were hydrolyzed by hNudt16 with a strong substrate preference for inosine or guanosine containing compounds. A new identified substrate for hNudt16, GppG, which binds the enzyme with an affinity comparable to that of IDP, suggests another potential regulatory role of this protein. Molecular docking of hNudt16-ligand binding inside the hNudt16 pocket revealed two binding modes for representative substrates. Nucleobase stabilization by Π stacking interactions with His24 has been associated with strong binding of hNudt16 substrates. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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18 pages, 2958 KiB  
Article
Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice
by Yang Yang, Xinyun Xu, Haoying Wu, Jun Yang, Jiangang Chen, Christophe Morisseau, Bruce D. Hammock, Ahmed Bettaieb and Ling Zhao
Int. J. Mol. Sci. 2021, 22(15), 8267; https://doi.org/10.3390/ijms22158267 - 31 Jul 2021
Cited by 9 | Viewed by 2933
Abstract
17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an [...] Read more.
17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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17 pages, 4040 KiB  
Article
The Consequences of Soluble Epoxide Hydrolase Deletion on Tumorigenesis and Metastasis in a Mouse Model of Breast Cancer
by Rushendhiran Kesavan, Timo Frömel, Sven Zukunft, Bernhard Brüne, Andreas Weigert, Ilka Wittig, Rüdiger Popp and Ingrid Fleming
Int. J. Mol. Sci. 2021, 22(13), 7120; https://doi.org/10.3390/ijms22137120 - 1 Jul 2021
Cited by 6 | Viewed by 3003
Abstract
Epoxides and diols of polyunsaturated fatty acids (PUFAs) are bioactive and can influence processes such as tumor cell proliferation and angiogenesis. Studies with inhibitors of the soluble epoxide hydrolase (sEH) in animals overexpressing cytochrome P450 enzymes or following the systemic administration of specific [...] Read more.
Epoxides and diols of polyunsaturated fatty acids (PUFAs) are bioactive and can influence processes such as tumor cell proliferation and angiogenesis. Studies with inhibitors of the soluble epoxide hydrolase (sEH) in animals overexpressing cytochrome P450 enzymes or following the systemic administration of specific epoxides revealed a markedly increased incidence of tumor metastases. To determine whether PUFA epoxides increased metastases in a model of spontaneous breast cancer, sEH-/- mice were crossed onto the polyoma middle T oncogene (PyMT) background. We found that the deletion of the sEH accelerated the growth of primary tumors and increased both the tumor macrophage count and angiogenesis. There were small differences in the epoxide/diol content of tumors, particularly in epoxyoctadecamonoenic acid versus dihydroxyoctadecenoic acid, and marked changes in the expression of proteins linked with cell proliferation and metabolism. However, there was no consequence of sEH inhibition on the formation of metastases in the lymph node or lung. Taken together, our results confirm previous reports of increased tumor growth in animals lacking sEH but fail to substantiate reports of enhanced lymph node or pulmonary metastases. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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14 pages, 1310 KiB  
Article
Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice
by Catherine M. Davis, Wenri H. Zhang, Elyse M. Allen, Thierno M. Bah, Robert E. Shangraw and Nabil J. Alkayed
Int. J. Mol. Sci. 2021, 22(11), 5419; https://doi.org/10.3390/ijms22115419 - 21 May 2021
Cited by 10 | Viewed by 1999
Abstract
Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces [...] Read more.
Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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15 pages, 1744 KiB  
Article
Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues
by Christophe Morisseau, Sean D. Kodani, Shizuo G. Kamita, Jun Yang, Kin Sing Stephen Lee and Bruce D. Hammock
Int. J. Mol. Sci. 2021, 22(9), 4993; https://doi.org/10.3390/ijms22094993 - 8 May 2021
Cited by 15 | Viewed by 2543
Abstract
Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for [...] Read more.
Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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10 pages, 9736 KiB  
Article
Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives
by Jan Madacki, Martin Kopál, Mary Jackson and Jana Korduláková
Int. J. Mol. Sci. 2021, 22(6), 2884; https://doi.org/10.3390/ijms22062884 - 12 Mar 2021
Cited by 2 | Viewed by 2174
Abstract
The genome of the human intracellular pathogen Mycobacterium tuberculosis encodes an unusually large number of epoxide hydrolases, which are thought to be involved in lipid metabolism and detoxification reactions needed to endure the hostile environment of host macrophages. These enzymes therefore represent suitable [...] Read more.
The genome of the human intracellular pathogen Mycobacterium tuberculosis encodes an unusually large number of epoxide hydrolases, which are thought to be involved in lipid metabolism and detoxification reactions needed to endure the hostile environment of host macrophages. These enzymes therefore represent suitable targets for compounds such as urea derivatives, which are known inhibitors of soluble epoxide hydrolases. In this work, we studied in vitro the effect of the thiourea drug isoxyl on six epoxide hydrolases of M. tuberculosis using a fatty acid substrate. We show that one of the proteins inhibited by isoxyl is EphD, an enzyme involved in the metabolism of mycolic acids, key components of the mycobacterial cell wall. By analyzing mycolic acid profiles, we demonstrate the inhibition of EphD epoxide hydrolase activity by isoxyl and two other urea-based inhibitors, thiacetazone and AU1235, inside the mycobacterial cell. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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Graphical abstract

22 pages, 2941 KiB  
Article
Soluble Epoxide Hydrolase in Aged Female Mice and Human Explanted Hearts Following Ischemic Injury
by K. Lockhart Jamieson, Ahmed M. Darwesh, Deanna K. Sosnowski, Hao Zhang, Saumya Shah, Pavel Zhabyeyev, Jun Yang, Bruce D. Hammock, Matthew L. Edin, Darryl C. Zeldin, Gavin Y. Oudit, Zamaneh Kassiri and John M. Seubert
Int. J. Mol. Sci. 2021, 22(4), 1691; https://doi.org/10.3390/ijms22041691 - 8 Feb 2021
Cited by 12 | Viewed by 3393
Abstract
Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) [...] Read more.
Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) into numerous lipid mediators, oxylipids, which are further metabolised by soluble epoxide hydrolase (sEH), reducing their activity. The objective of this study was to characterize oxylipid metabolism in the left ventricle (LV) following ischemic injury in females. Human LV specimens were procured from female patients with ischemic cardiomyopathy (ICM) or non-failing controls (NFC). Female C57BL6 (WT) and sEH null mice averaging 13–16 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD) to induce myocardial infarction. WT (wild type) mice received vehicle or sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB), in their drinking water ad libitum for 28 days. Cardiac function was assessed using echocardiography and electrocardiogram. Protein expression was determined using immunoblotting, mitochondrial activity by spectrophotometry, and cardiac fibre respiration was measured using a Clark-type electrode. A full metabolite profile was determined by LC–MS/MS. sEH was significantly elevated in ischemic LV specimens from patients, associated with fundamental changes in oxylipid metabolite formation and significant decreases in mitochondrial enzymatic function. In mice, pre-treatment with tAUCB or genetic deletion of sEH significantly improved survival, preserved cardiac function, and maintained mitochondrial quality following MI in female mice. These data indicate that sEH may be a relevant pharmacologic target for women with MI. Although future studies are needed to determine the mechanisms, in this pilot study we suggest targeting sEH may be an effective strategy for reducing ischemic injury and mortality in middle-aged females. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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20 pages, 5169 KiB  
Article
Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity
by Haley Overby, Yang Yang, Xinyun Xu, Katherine Graham, Kelsey Hildreth, Sue Choi, Debin Wan, Christophe Morisseau, Darryl C. Zeldin, Bruce D. Hammock, Shu Wang, Ahmed Bettaieb and Ling Zhao
Int. J. Mol. Sci. 2020, 21(19), 7039; https://doi.org/10.3390/ijms21197039 - 24 Sep 2020
Cited by 10 | Viewed by 3607
Abstract
Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH [...] Read more.
Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (t-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. t-TUCB promoted brown adipogenesis in vitro. Although t-TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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Graphical abstract

12 pages, 1550 KiB  
Article
The Antihypertensive Effect of Quercetin in Young Spontaneously Hypertensive Rats; Role of Arachidonic Acid Metabolism
by Fawzy Elbarbry, Khaled Abdelkawy, Nicholas Moshirian and Ahmed M. Abdel-Megied
Int. J. Mol. Sci. 2020, 21(18), 6554; https://doi.org/10.3390/ijms21186554 - 8 Sep 2020
Cited by 30 | Viewed by 2657
Abstract
Hypertension affects almost 50% of the adult American population. Metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the blood pressure-lowering potential of quercetin (QR), a naturally occurring polyphenol, and examines its [...] Read more.
Hypertension affects almost 50% of the adult American population. Metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the blood pressure-lowering potential of quercetin (QR), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered QR in drinking water at concentrations of 10, 30, and 60 mg/L. Blood pressure was monitored at seven-day intervals. After a total of seven weeks of treatment, rats were killed and kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Medium- and high-dose QR resisted the rise in blood pressure observed in the untreated SHR and significantly inhibited the activity of the CYP4A enzyme in renal cortical microsomes. The activity of the sEH enzyme in renal cortical cytosols was significantly inhibited only by the high QR dose. Our data not only demonstrate the antihypertensive effect of QR, but also provide a novel mechanism for its underlying cardioprotective properties. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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Review

Jump to: Editorial, Research

18 pages, 2170 KiB  
Review
Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism
by Jinhai Wang, Ying Fang, R. Andrea Fan and Christopher J. Kirk
Int. J. Mol. Sci. 2021, 22(21), 11595; https://doi.org/10.3390/ijms222111595 - 27 Oct 2021
Cited by 29 | Viewed by 3838
Abstract
The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic [...] Read more.
The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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12 pages, 1340 KiB  
Review
The Role of Glycoside Hydrolases in Phytopathogenic Fungi and Oomycetes Virulence
by Vahideh Rafiei, Heriberto Vélëz and Georgios Tzelepis
Int. J. Mol. Sci. 2021, 22(17), 9359; https://doi.org/10.3390/ijms22179359 - 28 Aug 2021
Cited by 59 | Viewed by 4465
Abstract
Phytopathogenic fungi need to secrete different hydrolytic enzymes to break down complex polysaccharides in the plant cell wall in order to enter the host and develop the disease. Fungi produce various types of cell wall degrading enzymes (CWDEs) during infection. Most of the [...] Read more.
Phytopathogenic fungi need to secrete different hydrolytic enzymes to break down complex polysaccharides in the plant cell wall in order to enter the host and develop the disease. Fungi produce various types of cell wall degrading enzymes (CWDEs) during infection. Most of the characterized CWDEs belong to glycoside hydrolases (GHs). These enzymes hydrolyze glycosidic bonds and have been identified in many fungal species sequenced to date. Many studies have shown that CWDEs belong to several GH families and play significant roles in the invasion and pathogenicity of fungi and oomycetes during infection on the plant host, but their mode of function in virulence is not yet fully understood. Moreover, some of the CWDEs that belong to different GH families act as pathogen-associated molecular patterns (PAMPs), which trigger plant immune responses. In this review, we summarize the most important GHs that have been described in eukaryotic phytopathogens and are involved in the establishment of a successful infection. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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10 pages, 12513 KiB  
Review
Catalytic Amyloids as Novel Synthetic Hydrolases
by Eva Duran-Meza and Rodrigo Diaz-Espinoza
Int. J. Mol. Sci. 2021, 22(17), 9166; https://doi.org/10.3390/ijms22179166 - 25 Aug 2021
Cited by 8 | Viewed by 2096
Abstract
Amyloids are supramolecular assemblies composed of polypeptides stabilized by an intermolecular beta-sheet core. These misfolded conformations have been traditionally associated with pathological conditions such as Alzheimer’s and Parkinson´s diseases. However, this classical paradigm has changed in the last decade since the discovery that [...] Read more.
Amyloids are supramolecular assemblies composed of polypeptides stabilized by an intermolecular beta-sheet core. These misfolded conformations have been traditionally associated with pathological conditions such as Alzheimer’s and Parkinson´s diseases. However, this classical paradigm has changed in the last decade since the discovery that the amyloid state represents a universal alternative fold accessible to virtually any polypeptide chain. Moreover, recent findings have demonstrated that the amyloid fold can serve as catalytic scaffolds, creating new opportunities for the design of novel active bionanomaterials. Here, we review the latest advances in this area, with particular emphasis on the design and development of catalytic amyloids that exhibit hydrolytic activities. To date, three different types of activities have been demonstrated: esterase, phosphoesterase and di-phosphohydrolase. These artificial hydrolases emerge upon the self-assembly of small peptides into amyloids, giving rise to catalytically active surfaces. The highly stable nature of the amyloid fold can provide an attractive alternative for the design of future synthetic hydrolases with diverse applications in the industry, such as the in situ decontamination of xenobiotics. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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10 pages, 1806 KiB  
Review
The Eyes Absent Proteins: Unusual HAD Family Tyrosine Phosphatases
by Kaushik Roychoudhury and Rashmi S. Hegde
Int. J. Mol. Sci. 2021, 22(8), 3925; https://doi.org/10.3390/ijms22083925 - 10 Apr 2021
Cited by 11 | Viewed by 2237
Abstract
Here, we review the haloacid dehalogenase (HAD) class of protein phosphatases, with a particular emphasis on an unusual group of enzymes, the eyes absent (EYA) family. EYA proteins have the unique distinction of being structurally and mechanistically classified as HAD enzymes, yet, unlike [...] Read more.
Here, we review the haloacid dehalogenase (HAD) class of protein phosphatases, with a particular emphasis on an unusual group of enzymes, the eyes absent (EYA) family. EYA proteins have the unique distinction of being structurally and mechanistically classified as HAD enzymes, yet, unlike other HAD phosphatases, they are protein tyrosine phosphatases (PTPs). Further, the EYA proteins are unique among the 107 classical PTPs in the human genome because they do not use a Cysteine residue as a nucleophile in the dephosphorylation reaction. We will provide an overview of HAD phosphatase structure-function, describe unique features of the EYA family and their tyrosine phosphatase activity, provide a brief summary of the known substrates and cellular functions of the EYA proteins, and speculate about the evolutionary origins of the EYA family of proteins. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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17 pages, 1077 KiB  
Review
The Multifaceted Role of Epoxide Hydrolases in Human Health and Disease
by Jérémie Gautheron and Isabelle Jéru
Int. J. Mol. Sci. 2021, 22(1), 13; https://doi.org/10.3390/ijms22010013 - 22 Dec 2020
Cited by 39 | Viewed by 4990
Abstract
Epoxide hydrolases (EHs) are key enzymes involved in the detoxification of xenobiotics and biotransformation of endogenous epoxides. They catalyze the hydrolysis of highly reactive epoxides to less reactive diols. EHs thereby orchestrate crucial signaling pathways for cell homeostasis. The EH family comprises 5 [...] Read more.
Epoxide hydrolases (EHs) are key enzymes involved in the detoxification of xenobiotics and biotransformation of endogenous epoxides. They catalyze the hydrolysis of highly reactive epoxides to less reactive diols. EHs thereby orchestrate crucial signaling pathways for cell homeostasis. The EH family comprises 5 proteins and 2 candidate members, for which the corresponding genes are not yet identified. Although the first EHs were identified more than 30 years ago, the full spectrum of their substrates and associated biological functions remain partly unknown. The two best-known EHs are EPHX1 and EPHX2. Their wide expression pattern and multiple functions led to the development of specific inhibitors. This review summarizes the most important points regarding the current knowledge on this protein family and highlights the particularities of each EH. These different enzymes can be distinguished by their expression pattern, spectrum of associated substrates, sub-cellular localization, and enzymatic characteristics. We also reevaluated the pathogenicity of previously reported variants in genes that encode EHs and are involved in multiple disorders, in light of large datasets that were made available due to the broad development of next generation sequencing. Although association studies underline the pleiotropic and crucial role of EHs, no data on high-effect variants are confirmed to date. Full article
(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism)
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