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The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress

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

Deadline for manuscript submissions: 1 July 2024 | Viewed by 8774

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Dr. Christophe Morisseau

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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
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Dear Colleagues,

Chemical exposure can profoundly affect our health. Some exposures are voluntary (food, drugs, etc.), and some are 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. In addition to some well-documented roles in the metabolism of foreign chemicals, recent findings demonstrate the biological roles of 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, in addition to their role in the metabolism of toxins and natural products.

Dr. Christophe Morisseau
Guest Editor

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Keywords

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

Published Papers (6 papers)

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Research

23 pages, 6154 KiB

Open AccessArticle

Expression, Characterisation, Homology Modelling and Molecular Docking of a Novel M17 Family Leucyl-Aminopeptidase from Bacillus cereus CZ

by Jie Liu and Tangbing Cui

Int. J. Mol. Sci. 2023, 24(21), 15939; https://doi.org/10.3390/ijms242115939 - 03 Nov 2023

Viewed by 755

Abstract

Leucyl-aminopeptidase (LAP), an important metallopeptidase, hydrolyses amino acid residues from the N-terminus of polypeptides and proteins, acting preferentially on the peptide bond formed by N-terminus leucine. A new leucyl-aminopeptidase was found in Bacillus cereus CZ. Its gene (bclap) contained a 1485 bp ORF encoding 494 amino acids with a molecular weight of 54 kDa. The bcLAP protein was successfully expressed in E. coli BL21(DE3). Optimal activity is obtained at pH 9.0 and 58 °C. The bcLAP displays a moderate thermostability and an alkaline pH adaptation range. Enzymatic activity is dramatically enhanced by Ni²⁺. EDTA significantly inhibits the enzymatic activity, and bestatin and SDS also show strong inhibition. The three-dimensional model of bcLAP monomer and homohexamer is simulated byPHYRE2 server and SWISS-MODEL server. The docking of bestatin, Leu-Trp, Asp-Trp and Ala-Ala-Gly to bcLAP is performed using AutoDock4.2.5, respectively. Molecular docking results show that the residues Lys260, Asp265, Lys272, Asp283, Asp342, Glu344, Arg346, Gly372 and His437 are involved in the hydrogen bonding with the ligands and zinc ions. There may be two nucleophilic catalytic mechanisms in bcLAP, one involving His 437 or Arg346 and the other involving His437 and Arg346. The bcLAP can hydrolyse the peptide bonds in Leu-Trp, Asp-Trp and Ala-Ala-Gly. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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12 pages, 1578 KiB

Open AccessArticle

The Generation of a Nanobody-Based ELISA for Human Microsomal Epoxide Hydrolase

by Qiyi He, Mark R. McCoy, Meng Qi, Christophe Morisseau, Huiyi Yang, Chengpeng Xu, Rachel Shey, Michael C. Goodman, Suqing Zhao and Bruce D. Hammock

Int. J. Mol. Sci. 2023, 24(19), 14698; https://doi.org/10.3390/ijms241914698 - 28 Sep 2023

Viewed by 1325

Abstract

A microsomal epoxide hydrolase (mEH) metabolizes in vivo in both xenobiotic and endogenous epoxides associated with signaling function. Findings in patients suggest that mEH might be a biomarker for several diseases, including metastatic cancer and viral hepatitis. To easily quantify mEH, nanobodies specific to the human mEH were isolated from a phage library of llama VHHs. Four unique clones were obtained and used for developing ELISAs. Three formats of double antibody sandwich assays were investigated using different detection strategies. Using PolyHRP, the signal was strongly amplified, yielding a 22-fold lower LOD (12 pg mL⁻¹) than the ‘conventional’. To further validate the performance of the immunoassays, human tissue samples were analyzed by nanobody-based ELISAs and compared to the enzyme activities (R² > 0.95). The results demonstrate that these nanobodies are powerful tools for the quantification of human mEH and could eventually result in a bedside assay. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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13 pages, 2640 KiB

Open AccessArticle

Effects of Individual Circulating FFAs on Plasma and Hepatic FFA Epoxides, Diols, and Epoxide-Diol Ratios as Indices of Soluble Epoxide Hydrolase Activity

by Young Taek Oh, Jun Yang, Christophe Morisseau, Qiyi He, Bruce Hammock and Jang H. Youn

Int. J. Mol. Sci. 2023, 24(13), 10760; https://doi.org/10.3390/ijms241310760 - 28 Jun 2023

Cited by 1 | Viewed by 772

Abstract

Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively (p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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12 pages, 1838 KiB

Open AccessArticle

Aflatoxin B₁ Increases Soluble Epoxide Hydrolase in the Brain and Induces Neuroinflammation and Dopaminergic Neurotoxicity

by Weicang Wang, Yuxin Wang, Karen M. Wagner, Ruth Diana Lee, Sung Hee Hwang, Christophe Morisseau, Heike Wulff and Bruce D. Hammock

Int. J. Mol. Sci. 2023, 24(12), 9938; https://doi.org/10.3390/ijms24129938 - 09 Jun 2023

Cited by 3 | Viewed by 1315

Abstract

Parkinson’s disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B₁ (AFB₁), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB₁ leads to neurological disorders as well as cancer. However, whether and how aflatoxin B₁ contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB₁ is shown to induce neuroinflammation, trigger the α-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB₁-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB₁ in vivo and in vitro. Together, our findings suggest a contributing role of AFB₁ to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB₁ exposure. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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12 pages, 1891 KiB

Open AccessArticle

Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon

by Weicang Wang, Karen M. Wagner, Yuxin Wang, Nalin Singh, Jun Yang, Qiyi He, Christophe Morisseau and Bruce D. Hammock

Int. J. Mol. Sci. 2023, 24(5), 4570; https://doi.org/10.3390/ijms24054570 - 26 Feb 2023

Cited by 2 | Viewed by 1944

Abstract

Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and β-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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25 pages, 2900 KiB

Open AccessArticle

The Interactions of the 70 kDa Fragment of Cell Adhesion Molecule L1 with Topoisomerase 1, Peroxisome Proliferator-Activated Receptor γ and NADH Dehydrogenase (Ubiquinone) Flavoprotein 2 Are Involved in Gene Expression and Neuronal L1-Dependent Functions

by Gabriele Loers, Ralf Kleene, Ute Bork and Melitta Schachner

Int. J. Mol. Sci. 2023, 24(3), 2097; https://doi.org/10.3390/ijms24032097 - 20 Jan 2023

Cited by 3 | Viewed by 1780

Abstract

The cell adhesion molecule L1 is essential not only for neural development, but also for synaptic functions and regeneration after trauma in adulthood. Abnormalities in L1 functions cause developmental and degenerative disorders. L1’s functions critically depend on proteolysis which underlies dynamic cell interactions and signal transduction. We showed that a 70 kDa fragment (L1-70) supports mitochondrial functions and gene transcription. To gain further insights into L1-70’s functions, we investigated several binding partners. Here we show that L1-70 interacts with topoisomerase 1 (TOP1), peroxisome proliferator-activated receptor γ (PPARγ) and NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2). TOP1, PPARγ and NDUFV2 siRNAs reduced L1-dependent neurite outgrowth, and the topoisomerase inhibitors topotecan and irinotecan inhibited L1-dependent neurite outgrowth, neuronal survival and migration. In cultured neurons, L1 siRNA reduces the expression levels of the long autism genes neurexin-1 (Nrxn1) and neuroligin-1 (Nlgn1) and of the mitochondrially encoded gene NADH:ubiquinone oxidoreductase core subunit 2 (ND2). In mutant mice lacking L1-70, Nrxn1 and Nlgn1, but not ND2, mRNA levels are reduced. Since L1-70’s interactions with TOP1, PPARγ and NDUFV2 contribute to the expression of two essential long autism genes and regulate important neuronal functions, we propose that L1 may not only ameliorate neurological problems, but also psychiatric dysfunctions. Full article

(This article belongs to the Special Issue The Role of Hydrolases in Biology and Xenobiotics Metabolism: Recent Progress)

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