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Survey of Ophthalmology 1988Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase.... (Review)
Review
Galactosemia is a disorder caused by a deficiency of any one of three possible enzymes involved in the metabolism of galactose: galactokinase, transferase or epimerase. Any single deficient enzyme can result in cataract through the accumulation of galactitol in the lens. The ophthalmologist may play an important role in this disease, since early recognition of cataract development followed by the initiation of a galactose-free diet may lead to clearing of lenticular opacities. The clinical and laboratory findings that distinguish the three enzyme deficiency disorders of galactosemia are discussed. The biochemical genetics of each enzyme also are reviewed, along with the recent evidence linking heterozygous galactokinase deficiency and presenile cataract.
Topics: Animals; Cataract; Female; Galactokinase; Galactose; Galactosemias; Genes; Humans; Methods; Molecular Biology; Pregnancy; Pregnancy Complications; UDPglucose 4-Epimerase; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 3043741
DOI: 10.1016/0039-6257(88)90095-1 -
The Biochemical Journal Dec 1996The enzymic stages of mammalian mitochondrial beta-oxidation were elucidated some 30-40 years ago. However, the discovery of a membrane-associated multifunctional enzyme... (Review)
Review
The enzymic stages of mammalian mitochondrial beta-oxidation were elucidated some 30-40 years ago. However, the discovery of a membrane-associated multifunctional enzyme of beta-oxidation, a membrane-associated acyl-CoA dehydrogenase and characterization of the carnitine palmitoyl transferase system at the protein and at the genetic level has demonstrated that the enzymes of the system itself are incompletely understood. Deficiencies of many of the enzymes have been recognized as important causes of disease. In addition, the study of these disorders has led to a greater understanding of the molecular mechanism of beta-oxidation and the import, processing and assembly of the beta-oxidation enzymes within the mitochondrion. The tissue-specific regulation, intramitochondrial control and supramolecular organization of the pathway is becoming better understood as sensitive analytical and molecular techniques are applied. This review aims to cover enzymological and organizational aspects of mitochondrial beta-oxidation together with the biochemical aspects of inherited disorders of beta-oxidation and the intrinsic control of beta-oxidation.
Topics: Acyl-CoA Dehydrogenases; Animals; Carnitine O-Palmitoyltransferase; Coenzyme A Ligases; Fatty Acids; Humans; Lipid Metabolism, Inborn Errors; Mammals; Mitochondria; Models, Biological; Oxidation-Reduction
PubMed: 8973539
DOI: 10.1042/bj3200345 -
Endocrine Reviews Apr 2019Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C... (Review)
Review
Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C enzymes acting as 3-ketosteroid, 17-ketosteroid, and 20-ketosteroid reductases are involved in the prereceptor regulation of ligands for the androgen, estrogen, and progesterone receptors and are considered drug targets to treat steroid hormone-dependent malignancies and endocrine disorders. In contrast, AKR1D1 is the only known steroid 5β-reductase and is essential for bile-acid biosynthesis, the generation of ligands for the farnesoid X receptor, and the 5β-dihydrosteroids that have their own biological activity. In this review we discuss the crystal structures of these AKRs, their kinetic and catalytic mechanisms, AKR genomics (gene expression, splice variants, polymorphic variants, and inherited genetic deficiencies), distribution in steroid target tissues, roles in steroid hormone action and disease, and inhibitor design.
Topics: Aldo-Keto Reductases; Humans; Hydroxysteroid Dehydrogenases; Oxidoreductases; Steroids
PubMed: 30137266
DOI: 10.1210/er.2018-00089 -
Biochimica Et Biophysica Acta Sep 2012Peroxisome biogenesis and peroxisomal β-oxidation defects are rare inherited metabolic disorders in which several organs can be affected. A panel of mouse models has... (Review)
Review
Peroxisome biogenesis and peroxisomal β-oxidation defects are rare inherited metabolic disorders in which several organs can be affected. A panel of mouse models has been created in which genes crucial to these processes were inactivated and the ensuing pathologies studied. In mice with enzyme defects of peroxisomal β-oxidation, the disease state strongly depends on the kind of substrates that are metabolized by the enzyme and the dietary composition. Because mice with generalized biogenesis defects seldom reach adulthood, conditional knockout models were generated to study the consequences of peroxisome deficiency in hepatocytes, different brain cell types and Sertoli cells. Although the precise relationship between the biochemical anomalies and pathologies was often not resolved, the mouse models allowed to document in detail histological abnormalities, metabolic and gene expression deregulations some of which are mediated by PPARα, and to uncover the essential role of peroxisomes in some unsuspected cell types.
Topics: Acyl-CoA Oxidase; Acyltransferases; Animals; Brain; Carrier Proteins; Disease Models, Animal; Enoyl-CoA Hydratase; Humans; Lipid Metabolism; Liver; Mice; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Racemases and Epimerases
PubMed: 22446031
DOI: 10.1016/j.bbadis.2012.03.003 -
Journal of Biochemistry Feb 2022Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as...
Substrate-derived biomarkers are necessary in slowly progressing monogenetic diseases caused by single-enzyme deficiencies to identify affected patients and serve as surrogate markers for therapy response. N-glycanase 1 (NGLY1) deficiency is an ultra-rare autosomal recessive disorder characterized by developmental delay, peripheral neuropathy, elevated liver transaminases, hyperkinetic movement disorder and (hypo)-alacrima. We demonstrate that N-acetylglucosamine-asparagine (GlcNAc-Asn; GNA), is the analyte most closely associated with NGLY1 deficiency, showing consistent separation in levels between patients and controls. GNA accumulation is directly linked to the absence of functional NGLY1, presenting strong potential for its use as a biomarker. In agreement, a quantitative liquid chromatography with tandem mass spectrometry assay, developed to assess GNA from 3 to 3000 ng/ml, showed that it is conserved as a marker for loss of NGLY1 function in NGLY1-deficient cell lines, rodents (urine, cerebrospinal fluid, plasma and tissues) and patients (plasma and urine). Elevated GNA levels differentiate patients from controls, are stable over time and correlate with changes in NGLY1 activity. GNA as a biomarker has the potential to identify and validate patients with NGLY1 deficiency, act as a direct pharmacodynamic marker and serve as a potential surrogate endpoint in clinical trials.
Topics: Asparagine; Biomarkers; Congenital Disorders of Glycosylation; Humans; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
PubMed: 34697629
DOI: 10.1093/jb/mvab111 -
FEBS Letters Feb 2020Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and... (Review)
Review
Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short-chain enoyl-CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1-deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1-deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.
Topics: Animals; Enoyl-CoA Hydratase; Fatty Acids; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 31944285
DOI: 10.1002/1873-3468.13735 -
Hormone Research 2008P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all... (Review)
Review
P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all microsomal P450 enzymes, including the three steroidogenic enzymes P450c17 (17alpha-hydroxylase/17,20-lyase), P450c21 (21-hydroxylase), and P450aro (aromatase). Since the first description of POR mutations in 2004, about 50 patients have been reported. Serum steroid profiles indicate partial deficiencies in 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase. The 17-OH progesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to adrenocorticotropic hormone. Most patients also have associated skeletal malfor- mations (craniosynostosis, radio-ulnar synostosis, midface hypoplasia, bowed femora) termed Antley-Bixler syndrome. Antley-Bixler syndrome with normal steroidogenesis is caused by autosomal dominant gain-of-function mutations in fibroblast growth factor receptor 2. Males with POR deficiency are often undervirilized, while females can be virilized. The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. The potential impact of POR mutations on drug metabolism by other hepatic P450 enzymes requires further investigation. Given the varied physical and biochemical phenotype of POR deficiency and the risk of adrenal insufficiency, clinicians should be alert to this potential diagnosis.
Topics: Abnormalities, Multiple; Bone and Bones; Cytochrome P-450 Enzyme System; Endocrine System Diseases; Humans; Hydroxysteroid Dehydrogenases; Models, Biological; NADH, NADPH Oxidoreductases; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase; Syndrome
PubMed: 18259105
DOI: 10.1159/000114857 -
Nutrients Dec 2021Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a... (Review)
Review
Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.
Topics: Amyotrophic Lateral Sclerosis; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Asthma; Carbonic Anhydrases; Cardiovascular Diseases; Enzymes; Homeostasis; Humans; Immune System; Metalloproteins; Micronutrients; Pulmonary Disease, Chronic Obstructive; Trace Elements; Zinc
PubMed: 34960004
DOI: 10.3390/nu13124456 -
Archives of Pathology & Laboratory... Dec 2000Partial succinate dehydrogenase deficiency (15% to 50% of normal reference enzyme activity) in skeletal muscle causes mitochondrial myopathy with various symptoms, for...
BACKGROUND
Partial succinate dehydrogenase deficiency (15% to 50% of normal reference enzyme activity) in skeletal muscle causes mitochondrial myopathy with various symptoms, for example, brain involvement, cardiomyopathy, and/or exercise intolerance. The deficiency may be isolated or may coexist with other respiratory-chain enzyme defects. The histopathologic assessment of succinate dehydrogenase activity in muscle biopsies of patients with suspected mitochondrial myopathies has focused on the finding of increased staining, usually in ragged-red fibers, rather than on reduced staining.
OBJECTIVES
To determine the prevalence of muscle succinate dehydrogenase deficiency among patients with respiratory-chain defects and to determine whether the reduced activity is present histochemically and is comparable to the quantitative reduction found in muscle homogenates.
PATIENTS AND METHODS
One hundred eight muscle biopsies were evaluated from patients with suspected mitochondrial myopathies by qualitative histochemical analysis and quantitative biochemical analyses of respiratory-chain enzymes using standard methodologies.
RESULTS
Fifty-two patients had defects in respiratory-chain complexes; of these patients, 12 (23%) had partial deficiencies in succinate dehydrogenase activity either alone or together with reductions in other enzymes. The reduced activity was detectable histochemically in muscle biopsies with residual enzyme activity of up to 34% of the normal reference activity, while 2 biopsies with higher residual activity (49% and 68% of normal) could not be distinguished from normal biopsies.
CONCLUSIONS
Of the patients with respiratory-chain enzyme defects, 23% had partial deficiencies of succinate dehydrogenase activity in muscle biopsies. This reduction could be detected histochemically in biopsies in most cases. The marked prevalence of succinate dehydrogenase deficiency among patients with respiratory-chain defects and its detection initially by histochemical analysis are important findings.
Topics: Adolescent; Adult; Aged; Biopsy; Child; Child, Preschool; Female; Histocytochemistry; Humans; Infant; Male; Middle Aged; Mitochondrial Myopathies; Muscle, Skeletal; Succinate Dehydrogenase
PubMed: 11100052
DOI: 10.5858/2000-124-1755-SDD -
Biological Chemistry Jun 2008Tissue kallikrein (KLK1) is a kinin-forming serine protease synthesized in many organs including arteries and kidney. Study of the physiological role of KLK1 has... (Review)
Review
Tissue kallikrein (KLK1) is a kinin-forming serine protease synthesized in many organs including arteries and kidney. Study of the physiological role of KLK1 has benefited from the availability of mouse and human genetic models of KLK1 deficiency, through engineering of KLK1 mouse mutants and discovery of a major polymorphism in the human KLK1 gene that induces a loss of enzyme activity. Studies in KLK1-deficient mice and human subjects partially deficient in KLK1 have documented its critical role in arterial function in both species. KLK1 is also involved in the control of ionic transport in the renal tubule, an action that may not be kinin-mediated. Studies of experimental diseases in KLK1-deficient mice have revealed cardio- and nephro-protective effects of KLK1 and kinins in acute cardiac ischemia, post-ischemic heart failure, and diabetes. Potential clinical and therapeutic developments are discussed.
Topics: Animals; Arteries; Heart; Humans; Kidney; Myocardium; Tissue Kallikreins
PubMed: 18627303
DOI: 10.1515/BC.2008.081