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Psychotherapy and Psychosomatics 2003
Topics: Depressive Disorder; Folic Acid Deficiency; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Polymorphism, Genetic
PubMed: 12601222
DOI: 10.1159/000068693 -
Trends in Microbiology Nov 1996
Review
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Microbial; Genes, Bacterial; Isoniazid; Mycobacterium tuberculosis; Oxidoreductases; Peroxidases; Peroxiredoxins
PubMed: 8950806
DOI: 10.1016/0966-842x(96)30030-9 -
The Journal of Nutrition Nov 2012Duodenal cytochrome b (Dcytb, Cybrd1) is a ferric reductase localized in the duodenum that is highly upregulated in circumstances of increased iron absorption. To...
Duodenal cytochrome b (Dcytb, Cybrd1) is a ferric reductase localized in the duodenum that is highly upregulated in circumstances of increased iron absorption. To address the contribution of Dcytb to total duodenal ferric reductase activity as well as its wider role in iron metabolism, we first measured duodenal ferric reductase activity in wild-type (WT) and Dcytb knockout (Dcytb(-/-)) mice under 3 conditions known to induce gut ferric reductase: dietary iron deficiency, hypoxia, and pregnancy. Dcytb(-/-) and WT mice were randomly assigned to control (iron deficiency experiment, 48 mg/kg dietary iron; hypoxia experiment, normal atmospheric pressure; pregnancy experiment, nonpregnant animals) or treatment (iron deficiency experiment, 2-3 mg/kg dietary iron; hypoxia experiment, 53.3 kPa pressure; pregnancy experiment, d 20 of pregnancy) groups and duodenal reductase activity measured. We found no induction of ferric reductase activity in Dcytb(-/-) mice under any of these conditions, indicating there are no other inducible ferric reductases present in the duodenum. To test whether Dcytb was required for iron absorption in conditions with increased erythropoietic demand, we also measured tissue nonheme iron levels and hematological indices in WT and Dcytb(-/-) mice exposed to hypoxia. There was no evidence of gross alterations in iron absorption, hemoglobin, or total liver nonheme iron in Dcytb(-/-) mice exposed to hypoxia compared with WT mice. However, spleen nonheme iron was significantly less (6.7 ± 1.0 vs. 12.7 ± 0.9 nmol · mg tissue(-1); P < 0.01, n = 7-8) in hypoxic Dcytb(-/-) compared with hypoxic WT mice and there was evidence of impaired reticulocyte hemoglobinization with a lower reticulocyte mean corpuscular hemoglobin (276 ± 1 vs. 283 ± 2 g · L(-1); P < 0.05, n = 7-8) in normoxic Dcytb(-/-) compared with normoxic WT mice. We therefore conclude that DCYTB is the primary iron-regulated duodenal ferric reductase in the gut and that Dcytb is necessary for optimal iron metabolism.
Topics: Anemia, Iron-Deficiency; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cytochrome b Group; Diet; Duodenum; Erythropoiesis; Female; Gene Expression Regulation, Enzymologic; Hypoxia; Iron; Male; Mice; Mice, Knockout; Oxidoreductases; Oxygen; Pregnancy; Random Allocation; Spleen
PubMed: 22990466
DOI: 10.3945/jn.112.160358 -
Journal of Lipid Research Jun 1996The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol... (Review)
Review
The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. As a result, deficient cholesterol is produced and the precursor 7-dehydrocholesterol and derivatives (8-dehydrocholesterol and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol) accumulate. Tissues (especially brain) deprived of cholesterol, or because of the deposited sterol precursors and derivatives, develop abnormally and function poorly. Replacement with dietary cholesterol may help correct the biochemical defects and improve symptoms.
Topics: Adolescent; Adult; Child; Child, Preschool; Cholesterol; Dehydrocholesterols; Female; Fetal Death; Heterozygote; Humans; Incidence; Infant; Infant, Newborn; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Smith-Lemli-Opitz Syndrome
PubMed: 8808751
DOI: No ID Found -
Clinical Genetics Nov 2005Recent insights into the Smith-Lemli-Opitz syndrome. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation... (Review)
Review
Recent insights into the Smith-Lemli-Opitz syndrome. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation disorder caused by an inborn error of post-squalene cholesterol biosynthesis. Deficient cholesterol synthesis in SLOS is caused by inherited mutations of 3beta-hydroxysterol-Delta7 reductase gene (DHCR7). DHCR7 deficiency impairs both cholesterol and desmosterol production, resulting in elevated 7DHC/8DHC levels, typically decreased cholesterol levels and, importantly, developmental dysmorphology. The discovery of SLOS has led to new questions regarding the role of the cholesterol biosynthesis pathway in human development. To date, a total of 121 different mutations have been identified in over 250 patients with SLOS who represent a continuum of clinical severity. Two genetic mouse models have been generated which recapitulate some of the developmental abnormalities of SLOS and have been useful in elucidating the pathogenesis. This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS.
Topics: Animals; Base Sequence; Cholesterol; Genotype; Humans; Mice; Mutation; Oxidoreductases Acting on CH-CH Group Donors; Phenotype; Smith-Lemli-Opitz Syndrome
PubMed: 16207203
DOI: 10.1111/j.1399-0004.2005.00515.x -
International Journal of Molecular... Jan 2023Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the... (Review)
Review
Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in , , and genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.
Topics: Male; Humans; Aldo-Keto Reductases; Germ-Line Mutation; Oxidoreductases; Steroids; Hormones; Membrane Proteins; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
PubMed: 36768194
DOI: 10.3390/ijms24031873 -
Biochimica Et Biophysica Acta Aug 2000Membrane-bound succinate dehydrogenases (succinate:quinone reductases, SQR) and fumarate reductases (quinol:fumarate reductases, QFR) couple the oxidation of succinate... (Review)
Review
Membrane-bound succinate dehydrogenases (succinate:quinone reductases, SQR) and fumarate reductases (quinol:fumarate reductases, QFR) couple the oxidation of succinate to fumarate to the reduction of quinone to quinol and also catalyse the reverse reaction. SQR (respiratory complex II) is involved in aerobic metabolism as part of the citric acid cycle and of the aerobic respiratory chain. QFR is involved in anaerobic respiration with fumarate as the terminal electron acceptor, and is part of an electron transport chain catalysing the oxidation of various donor substrates by fumarate. QFR and SQR complexes are collectively referred to as succinate:quinone oxidoreductases (EC 1.3.5.1), have very similar compositions and are predicted to share similar structures. The complexes consist of two hydrophilic and one or two hydrophobic, membrane-integrated subunits. The larger hydrophilic subunit A carries covalently bound flavin adenine dinucleotide and subunit B contains three iron-sulphur centres. QFR of Wolinella succinogenes and SQR of Bacillus subtilis contain only one hydrophobic subunit (C) with two haem b groups. In contrast, SQR and QFR of Escherichia coli contain two hydrophobic subunits (C and D) which bind either one (SQR) or no haem b group (QFR). The structure of W. succinogenes QFR has been determined at 2.2 A resolution by X-ray crystallography (C.R.D. Lancaster, A. Kröger, M. Auer, H. Michel, Nature 402 (1999) 377-385). Based on this structure of the three protein subunits and the arrangement of the six prosthetic groups, a pathway of electron transfer from the quinol-oxidising dihaem cytochrome b to the site of fumarate reduction and a mechanism of fumarate reduction was proposed. The W. succinogenes QFR structure is different from that of the haem-less QFR of E. coli, described at 3.3 A resolution (T.M. Iverson, C. Luna-Chavez, G. Cecchini, D.C. Rees, Science 284 (1999) 1961-1966), mainly with respect to the structure of the membrane-embedded subunits and the relative orientations of soluble and membrane-embedded subunits. Also, similarities and differences between QFR transmembrane helix IV and transmembrane helix F of bacteriorhodopsin and their implications are discussed.
Topics: Animals; Binding Sites; Crystallography, X-Ray; Electron Transport; Electron Transport Complex II; Escherichia coli; Flavoproteins; Humans; Iron-Sulfur Proteins; Membrane Potentials; Membrane Proteins; Models, Chemical; Models, Molecular; Molecular Structure; Multienzyme Complexes; Oxidoreductases; Succinate Dehydrogenase; Wolinella
PubMed: 11004459
DOI: 10.1016/s0005-2728(00)00180-8 -
The American Journal of Clinical... Jan 2005The first step in iron absorption requires the reduction of ferric iron to ferrous iron, a change that is catalyzed by duodenal ferric reductase. Iron deficiency is...
BACKGROUND
The first step in iron absorption requires the reduction of ferric iron to ferrous iron, a change that is catalyzed by duodenal ferric reductase. Iron deficiency is associated with high iron absorption, high ferric reductase activity, and high duodenal ascorbate concentrations in experimental animals, but it is not known whether a relation between reductase and ascorbate is evident in humans.
OBJECTIVE
The objective of the study was to assess the relation between ferric reductase activity in human duodenal biopsy specimens and ascorbate concentrations in iron-replete and iron-deficient subjects.
DESIGN
Patients and control subjects were overnight-fasted adults presenting sequentially for upper gastrointestinal endoscopic investigation. Ferric reductase activity in duodenal biopsy specimens was assayed by using nitroblue tetrazolium. Ascorbate was assayed in duodenal biopsy specimens and plasma.
RESULTS
Iron-deficient patients had significantly higher reductase activity (n = 6-9; P < 0.05) and duodenal (n = 20; P < 0.001) and plasma (n = 6; P < 0.001) ascorbate concentrations than did control subjects. Incubation of biopsy specimens with dehydroascorbate (to boost cellular ascorbate) increased reductase activity in the tissues that initially had normal activity (n = 9; P < 0.01) but inhibited reductase activity in the tissues that already had high reductase activity (n = 13; P < 0.001).
CONCLUSIONS
Iron deficiency in humans is associated with increased duodenal ascorbate concentrations. This finding suggests that increased reductase activity is partly due to an increase in this substrate for duodenal cytochrome b reductase 1.
Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Case-Control Studies; Duodenum; FMN Reductase; Female; Humans; Intestinal Absorption; Iron; Iron Deficiencies; Male; Middle Aged
PubMed: 15640471
DOI: 10.1093/ajcn/81.1.130 -
Trends in Pharmacological Sciences Apr 2016Nox/Duox NADPH oxidases are now considered the primary, regulated sources of reactive oxygen species (ROS). These enzymes are expressed in diverse cells and tissues, and... (Review)
Review
Nox/Duox NADPH oxidases are now considered the primary, regulated sources of reactive oxygen species (ROS). These enzymes are expressed in diverse cells and tissues, and their products are essential in several physiological settings. Knockout mouse models are instrumental in identifying the physiological functions of Nox/Duox enzymes as well as in exploring the impact of their pharmacological targeting on disease progression. The currently available data from experiments on knockout animals suggest that the lack of non-phagocytic Nox/Duox enzymes often modifies the course and phenotype in many disease models. Nevertheless, as illustrated by studies on Nox4-deficient animals, the absence of Nox-derived ROS can also lead to aggravated disease manifestation, reinforcing the need for a more balanced view on the role of ROS in health and disease.
Topics: Animals; Humans; Mice; Mice, Knockout; NADH, NADPH Oxidoreductases
PubMed: 26861575
DOI: 10.1016/j.tips.2016.01.006 -
Redox Biology May 2021HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2)...
HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2) is primarily responsible for detoxifying ethanol-derived acetaldehyde and endogenous lipid aldehydes derived from lipid peroxidation. Epidemiological and Genome Wide Association Studies (GWAS) have linked an inactive ALDH2 rs671 variant, responsible for alcohol flush in nearly 8% world population and 40% of Asians, with cholesterol levels and higher risk of cardiovascular disease (CVD) but the underlying mechanism remains elusive. Here we find that the cholesterol levels in the serum and liver of ALDH2 knockout (AKO) and ALDH2 rs671 knock-in (AKI) mice are significantly increased, consistent with the increase of intermediates in the cholesterol biosynthetic pathways. Mechanistically, mitochondrial ALDH2 translocates to the endoplasmic reticulum to promote the formation of GP78/Insig1/HMGCR complex to increase HMGCR degradation through ubiquitination. Conversely, ALDH2 mutant or ALDH2 deficiency in AKI or AKO mice stabilizes HMGCR, resulting in enhanced cholesterol synthesis, which can be reversed by Lovastatin. Moreover, ALDH2-regulated cholesterol synthesis is linked to the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). Together, our study has identified that ALDH2 is a novel regulator of cholesterol synthesis, which may play an important role in CVD.
Topics: Acyl Coenzyme A; Aldehyde Dehydrogenase, Mitochondrial; Aldehyde Oxidoreductases; Animals; Cholesterol; Genome-Wide Association Study; Hydroxymethylglutaryl CoA Reductases; Liver; Mice
PubMed: 33740503
DOI: 10.1016/j.redox.2021.101919