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September 1982 - present
Publications
Publications (463)
The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15...
Background
Alzheimer’s disease (AD) is the most common human neurodegenerative disorder worldwide. Owing to its chronic nature, our limited understanding of its pathophysiological mechanisms, and because of the lack of effective anti-AD drugs, AD represents a significant socio-economic challenge for all industrialized countries. Neuronal cell death...
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a l...
Ferroptosis is a special kind of programmed cell death that has been implicated in the pathogenesis of a large number of human diseases. It involves dysregulated intracellular iron metabolism and uncontrolled lipid peroxidation, which together initiate intracellular ferroptotic signalling pathways leading to cellular suicide. Pharmacological interf...
Arachidonic acid 15-lipoxygenases (ALOX15) play a role in mammalian erythropoiesis but they have also been implicated in inflammatory processes. Seven intact Alox genes have been detected in the mouse reference genome and the mouse Alox15 gene is structurally similar to the orthologous genes of other mammals. However, mouse and human ALOX15 ortholo...
The human genome involves six functional arachidonic acid lipoxygenase (ALOX) genes and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiation and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. In other vertebrates, ALOX-isoforms have...
Background, objectives and design
Arachidonic acid 15-lipoxygenase (ALOX15) has been implicated in the pathogenesis of inflammatory diseases but since pro- and anti-inflammatory roles have been suggested, the precise function of this enzyme is still a matter of discussion. To contribute to this discussion, we created transgenic mice, which express...
Mammalian 15-lipoxygenases (ALOX15) are lipid peroxidizing enzymes that exhibit variable functionality in different cancer and inflammation models. The pathophysiological role of linoleic acid- and arachidonic acid-derived ALOX15 metabolites rendered this enzyme a target for pharmacological research. Several indole and imidazole derivatives inhibit...
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15...
The arachidonic acid lipoxygenase 15B (ALOX15B) orthologs of men and mice form different reaction products when arachidonic acid is used as the substrate. Tyr603Asp+His604Val double mutation in mouse arachidonic acid lipoxygenase 15b humanized the product pattern and an inverse mutagenesis strategy murinized the specificity of the human enzyme. As...
Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory, hyperproliferative, neurodegenerative, and metabolic diseases, but the physiological function of ALOX15 still remains a matter of discussion. To contribute to this discussion, we created transgenic mice (aP2-ALOX15 mice) expressing human ALOX15 under the...
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and h...
Eicosanoids and related compounds are pleiotropic lipid mediators, which are biosynthesized in mammals via three distinct metabolic pathways (cyclooxygenase pathway, lipoxygenase pathway, epoxygenase pathway). These mediators have been implicated in the pathogenesis of inflammatory diseases and drugs interfering with eicosanoid signaling are curren...
The guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein of the heterogenous nuclear ribonucleoprotein H/F (hnRNP H/F) family that binds to guanine-rich RNA sequences forming G-quadruplex structures. In mice and humans there are single copy GRSF1 genes, but multiple transcripts have been reported. GRSF1 has been implicated i...
Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and co...
Glutathione peroxidase 4 (Gpx4) and arachidonic acid 15 lipoxygenase (Alox15) are counterplayers in oxidative lipid metabolism and both enzymes have been implicated in spermatogenesis. However, the roles of the two proteins in acrosomal exocytosis have not been explored in detail. Here we characterized Gpx4 distribution in mouse sperm and detected...
Lipoxygenases (LOX) are a family lipid oxygenating enzymes that can generate bioactive lipids of clinical relevance from polyunsaturated fatty acids. Most LOXs display a Ca²⁺-dependent association with membranes for their activity. Nanodiscs (ND) are stable self-assembled discoidal fragments of lipid bilayers that can mimic the plasma membrane. In...
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and h...
CITATIONS 0 READS 129 60 authors, including: Some of the authors of this publication are also working on these related projects: SafeConsume View project O perfil epidemiológico e demográfico dos pacientes com tumor da cabeça e pescoço HPV16+ numa instituição oncológica em Portugal View project
Arachidonic acid lipoxygenases (ALOXs) have been implicated in the immune response of mammals. The reaction specificity of these enzymes is decisive for their biological functions and ALOX classification is based on this enzyme property. Comparing the amino acid sequences and the functional properties of selected mammalian ALOX15 orthologs we previ...
4open, its Editorial Board, scientists, and the network of the Theodor-Billroth-Academy and its International Consortium of Research Excellence (INCORE) are aware of the current dire situation for Ukrainian scientists and students.
After the unprovoked attack on Ukraine on February 24, 2022, our colleagues in Ukraine are now in fear for their fam...
4open, its Editorial Board, scientists, and the network of the Theodor-Billroth-Academy and its International Consortium of Research Excellence (INCORE) are aware of the current dire situation for Ukrainian scientists and students. After the unprovoked attack on Ukraine on February 24, 2022, our colleagues in Ukraine are now in fear for their famil...
Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of ox...
Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genom...
Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid o...
Among the eight human glutathione peroxidase isoforms, glutathione peroxidase 4 (GPX4) is the only enzyme capable of reducing complex lipid peroxides to the corresponding alcohols. In mice, corruption of the Gpx4 gene leads to embryonic lethality and more detailed expression silencing studies have implicated the enzyme in several physiological proc...
Background
RS75091 is a cinnamic acid derivative that has been used for the crystallization of the rabbit ALOX15-inhibitor complex. The atomic coordinates of the resolved ALOX15-inhibitor complex were later used to define the binding sites of other mammalian lipoxygenase orthologs, for which no direct structural data with ligand has been reported s...
Background
One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy....
Arachidonic acid lipoxygenases (ALOXs) have been suggested to function as monomeric enzymes, but more recent data on rabbit ALOX15 indicated that there is a dynamic monomer-dimer equilibrium in aqueous solution. In the presence of an active site ligand (the ALOX15 inhibitor RS7) rabbit ALOX15 was crystalized as heterodimer and the X-ray coordinates...
An increased omega‐3 polyunsaturated fatty acid (n‐3 PUFA) tissue status can lead to a significant formation of anti‐inflammatory lipid mediators and effective reduction in inflammation and tissue injury in murine colitis. Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory bowel disease as well as in the...
Endocannabinoids, such as anandamide (ANA) and 2-arachidonoylglycerol (2AG), are lipid-signaling molecules that can be oxidized by lipid-peroxidizing enzymes, and this oxidation alters the bioactivity of these lipid mediators. Here, under strictly comparable experimental conditions, we explored whether ANA and 2AG function as substrates for four hu...
In eukaryotic cells RNA-binding proteins have been implicated in virtually all post-transcriptional mechanisms of gene expression regulation. Based on the structural features of their RNA binding domains these proteins have been divided into several subfamilies. The presence of at least two RNA recognition motifs defines the group of heterogenous n...
Background: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Further, the likelihood of drug resistance is reduced. Distinct alterations in tumour metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Re...
Previously we have shown that among 15 substituted salicyloyl 5-seleninic acids (SSAs) 4 compounds with long side chains or a cyclohexyl group exhibit no glutathione peroxidase (GPx)-like activity in the coupled reductase model. Chemical reactions of one of the 4 inactive compounds with glutathione (GSH) and hydorperoxide, and experimental inhibiti...
Arachidonic acid 15‐lipoxygenases (ALOX15) are lipid peroxidizing enzymes, which has previously been implicated in the maturational breakdown of intracellular organelles and plasma membrane remodeling during reticulocyte‐erythrocyte transition. Conventional Alox15−/− mice are viable, develop normally but do not exhibit a major defective erythropoie...
Background and aims:
Oxidation of low-density lipoprotein (LDL) and oxidized LDL-mediated activation of the innate immune system have been recognized as early key events during the pathogenesis of atherosclerosis. Recent evidence identified eosinophils as a major source of enzymatic lipid oxidation and suggested a potential role of type 2 immunity...
Lipoxygenases (ALOX) are lipid peroxidizing enzymes that catalyze the biosynthesis of pro- and anti-inflammatory lipid mediators and have been implicated in (patho-)physiological processes. In humans, six functional ALOX isoforms exist and their arachidonic acid oxygenation products have been characterized. Products include leukotrienes and lipoxin...
After 300 million years of evolution, the first land‐living mammals reentered the marine environment some 50 million years ago. The driving forces for this dramatic lifestyle change are still a matter of discussion but the struggle for food resources and the opportunity to escape predators probably contributed. Reentering the oceans requires metabo...
PurposeIn the past, a role of thyroid hormones in human evolution has been hypothesized. T3, the metabolically active form, derives from extrathyroidal conversion of T4 by deionidase 2 (D2) enzyme encoded by DIO2 gene. In thyroid-deficient patients, decreased levels of free T3 have been associated with the polymorphism rs225014 A/G in DIO2, which c...
His596 of human ALOX12 has been suggested to interact with the COO⁻-group of arachidonic acid during ALOX catalysis. In mammalian ALOX15 orthologs Gln596 occupies this position and this amino acid exchange might contribute to the functional differences between the two ALOX-isoforms. To explore the role of Gln596 for ALOX15 functionality we mutated...
Purpose:
Lipoxygenases (LOX) have been implicated in carcinogenesis, however both pro- and anti-carcinogenic effects have been reported in different cancer models. Using transgenic mice, which specifically overexpress human 15-lipoxygenase (ALOX15) in endothelial cells (EC), we previously demonstrated significant inhibition of tumor development. I...
For the specificity of ALOX15 orthologs of different mammals the geometry of the amino acids Phe353, Ile418, Met419 and Ile593 (“triad determinants”) is important and mutagenesis of these residues altered the reaction specificity of these enzymes. Here we expressed wildtype human ALOX5 and its F359W/A424I/N425M/A603I mutant in Sf9 insect cells and...
Aims:
Most mammalian genomes involve several genes encoding for functionally distinct ALOX-isoforms. Pro-inflammatory leukotrienes are formed via the ALOX5 pathway but 12/15-lipoxygenating ALOX-isoforms have been implicated in the biosynthesis of pro-resolving mediators. In vitro mutagenesis of the triad determinants abolished the leukotriene synt...
The tree shrew (Tupaia belangeri) is a rat-sized mammal, which is more closely related to humans than mice and rats. However, the use of tree shrew to explore the patho-mechanisms of human inflammatory disorders has been limited since nothing is known about eicosanoid metabolism in this mammalian species. Eicosanoids are important lipid mediators e...
Background:
Atopic diseases constitute a major health challenge for industrialized countries, and elevated levels of interleukin 4 (IL-4) frequently characterize these disorders. Previous in vitroanalyses have indicated that IL-4 strongly upregulates the expression of IL-4-sensitive genes in human monocytes.
Objective:
To explore whether similar...
Lipoxygenases are lipid peroxidizing enzymes, which frequently occur in higher plants and mammals. These enzymes are also expressed in lower multicellular organisms but here they are not widely distributed. In bacteria, lipoxygenases rarely occur and evaluation of the currently available bacterial genomes suggested that <0.5% of all sequenced bacte...
Arachidonic acid lipoxygenases (ALOXs) are lipid-metabolizing enzymes that have been implicated in cell differentiation, but also in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. Most mammalian genomes involve six or seven functional ALOX genes and among the corresponding ALOX-isoforms the ALOX15 orthologs are some...
Lipoxygenases are lipid peroxidizing enzymes, which frequently occur in higher plants and animals. In bacteria, these enzymes are rare and have been introduced via horizontal gene transfer. Since viruses function as horizontal gene transfer vectors and since lipoxygenases may be helpful for releasing assembled virus particles from host cells we exp...
Background:
Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for inflammatory, hyperproliferative and neurodegenerative diseases. Pro-inflammatory eicosanoids have been implicated in the pathogenesis of multiple sclerosis since they augment vascular permeability and induce leukocyt...
The reaction specificity of lipoxygenases (ALOX) impacts the biological activity of these enzymes and also constitutes the decisive parameter for enzyme classification. ALOX15 orthologs, commonly known as 12/15-lipoxygenases, have recently been suggested to exhibit mainly arachidonic acid 12-lipoxygenating specificity in mammals ranked in evolution...
Glutathione peroxidases (GPX) are anti-oxidative enzymes that reduce organic and inorganic hydroperoxides to the corresponding alcohols at the expense of reduced glutathione. The human genome involves eight GPX genes and five of them encode for selenocysteine-containing enzymes. Among the human GPX-isoforms, GPX4 is unique since it is capable of re...
Lipoxygenases (ALOX) are involved in the regulation of cellular redox homeostasis. They also have been implicated in the biosynthesis of pro- and anti-inflammatory lipid mediators and play a role in the pathogenesis of inflammatory diseases, which constitute a major health challenge owing to increasing incidence and prevalence in all industrialized...
Previously we have shown that some of 5-selenized salicylic acid derivatives exhibit glutathione peroxidase (GPx)-like activities higher than or equal to ebselen [Yu et al., Chem. Eur. J., 2008, 14, 7066; Org. Biomol. Chem., 2010, 8, 828]. For understanding the absence of GPx-like activity of the homologue of 5-seleninic anhydride of salicyloylglyc...
Incubation of A549 cells in the absence and in the presence of pure recombinant PA-LOX. Pre-confluent A549 cells were incubated in the absence (videos 1–4) and presence (videos 5–8) of 250 μg/ml pure recombinant PA-LOX for 16 h in 8-well plates (assay volume 200 μl). The objective (20 × DIC) of the microscope (A1Rsi + Confocal System with Nikon Ecl...
The guanine-rich RNA sequence binding factor 1 (GRSF1) constitutes an ubiquitously occurring RNA-binding protein (RBP), which belongs to the family of heterogeneous nuclear ribonucleoprotein F/H (hnRNP F/H). It has been implicated in nuclear, cytosolic and mitochondrial RNA metabolism. Although the crystal structures of GRSF1 orthologs have not bee...
The Guanine-rich RNA sequence binding factor 1 (GRSF1) is a member of the heterogeneous nuclear ribonucleoprotein F/H family and has been implicated in RNA processing, RNA transport and translational regulation. Amino acid alignments and homology modeling suggested the existence of three distinct RNA-binding domains and two auxiliary domains. Unfor...
The reaction specificity of lipoxygenases is of physiological relevance since the various oxygenation products exhibit different biological activities. Among mammalian ALOX15 orthologs there are arachidonic acid 12- and 15-lipoxygenating enzymes and recent studies suggested an evolutionary switch in that reaction specificity during late primate dev...
Pseudomonas aeruginosa is a gram-negative pathogen, which causes life-threatening infections in immunocompromized patients. These bacteria express a secreted lipoxygenase (PA-LOX), which oxygenates free arachidonic acid to 15S-hydro(pero)xyeicosatetraenoic acid. It binds phospholipids at its active site and physically interacts with lipid vesicles....
Mammalian lipoxygenases (LOX) have been implicated in cell differentiation and in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. Although the reaction specificity of mammalian LOX with n-6 fatty acids (linoleic acid, arachidonic acid) has been explored in detail little information is currently available on the produ...
The authors would like to amend a sentence in the section 2.3. RNA preparation, reverse transcription and RT-PCR of Materials & Methods as below: The downstream primer was identical for amplification of all transcripts (5′-TCCAGTGTGAGACCCCTCTC-3′) but the upstream primers varied in sequence: ALOX2 (upstream 5′ AGCGATCGAGAATCTGTATGTG-3′), ALOX3a (up...
Molecular dynamics simulations and quantum mechanics/molecular mechanics calculations were performed on the in silico Leu597Ala/Ile663Ala double mutant of rabbit ALOX15 (12/15 lipoxygenase). The computational results suggested that subtle steric hindrance by the conserved Leu597 and C-terminal Ile663 residues disturbed H10 abstractions in wildtype...
Glutathione peroxidase 4 (GPX4) and arachidonic acid 15-lipoxygenase (ALOX15) are antagonizing enzymes in the metabolism of hydroperoxy lipids. In spermatoid cells and/or in the male reproductive system both enzymes are apparently expressed and GPX4 serves as anti-oxidative enzyme but also as structural protein. In this study we explored whether ge...
Significance
Lipoxygenases are lipid-peroxidizing enzymes that have been classified according to their reaction specificity. ALOX15 (12/15-lipoxygenase) has been implicated in inflammatory resolution via biosynthesis of antiinflammatory and proresolving lipoxins. We found that lower mammals including lower primates express arachidonic acid 12-lipox...
Molecular dynamics simulations and quantum mechanics/molecular mechanics calculations have been carried out on the in silico Leu597Ala/Ile663Ala double mutant of rabbit ALOX15. The computational results suggest that a subtle steric hindrance by the conserved Leu597 and C terminal Ile663 residues disturbs H10 abstractions in wild-type ALOX15 (which...
Lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which have been implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. They occur in bacteria and eucarya and the human genome involves six functional LOX genes, which encode for six different LOX i...
Lipoxygenases (LOX) are lipid-peroxidizing enzymes that play a role in cell differentiation, but have also been
implicated in the pathogenesis of inflammatory, hyperproliferative and neurological disorders. They are widely
distributed in plants and mammals but also occur sporadically in lower organisms. The human genome involves six functional LOX...
Pseudomonas aeruginosa (PA) expresses a secreted lipoxygenase (LOX), which oxygenates free arachidonic acid predominantly to 15S-H(p)ETE. The enzyme is capable of binding phospholipids at its active site and physically interacts with model membranes. However, its membrane oxygenase activity has not been quantified. To address this question, we over...
Among lipoxygenases ALOX15 orthologs are somewhat peculiar because of their capability of oxygenating polyenoic fatty acids even if they are incorporated in complex lipid-protein assemblies. ALOX15 orthologs of different species have been characterized before, but little is known about the corresponding rat enzyme. Since rats are frequently employe...
Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy...
Leukotrienes are pro-inflammatory lipid mediators, which are biosynthesized via the lipoxygenase pathway of the arachidonic acid cascade. Lipoxygenases form a family of lipid peroxidizing enzymes and human lipoxygenase isoforms have been implicated in the pathogenesis of inflammatory, hyperproliferative (cancer) and neurodegenerative diseases. Lipo...
Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins app...
Aims:
Glutathione peroxidases (Gpx) and lipoxygenases (Alox) are functional counterplayers in the metabolism of hydroperoxy lipids that regulate cellular redox homeostasis. Gpx4 is a moonlighting protein that has been implicated not only as an enzyme in anti-oxidative defense, gene expression regulation, and programmed cell death, but also as a st...
Induction of cell proliferation requires a concomitant increase in the synthesis of
glycosylated lipids and membrane proteins, which is dependent on ER-Golgi protein
transport by CopII-coated vesicles. In this process, retrograde transport of ER resident
proteins from the Golgi is crucial to maintain ER integrity, and allows for anterograde
transpo...
The development of the embryo depends on a sequence of tightly regulated events. A multitude of regulatory networks facilitate spatial and temporal control of embryo development and ascertain that the embryo proceeds safely through the developmental stages. During this process, the embryo encounters changing environmental conditions that may affect...
