Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In research on congenital metabolic disorders, a biochemist can choose between the theoretical and the practical approach. The diagnosis of metabolic diseases relies on 1) the determination of the presence of metabolites under normal conditions that are direct substrates of the defective enzyme (e.g., the Gm2 ganglioside in the brain tissue of a patient with Tay-Sachs disease); 2) the determination of the lack or insufficiency of the direct product of the defective enzyme (e.g., aryl sulfatase A in the cells of patients with metachromatic leukodystrophy), hormone (hypothyroidism), or receptor (congenital hypercholesterolemia); 3) determination of substance whose reduction was established by experimentation, but the cause of the decrease is not known (ceruloplasmin in Wilson's disease); and 4) DNA analysis. Metabolic impairment of genetic origin is not treatable. The disease can be prevented by 1) removing the inappropriate metabolite (e.g., copper accumulation can be avoided by giving penicillamine or zinc salts); 2) limiting those substances in the critical phase of childhood that are components of the defective enzyme (e.g. gluten reduction in colic and protein in phenylketonuria); 3) supplementing the insufficient metabolite (e.g., phosphate in hypophosphatemia by sound for 12 hours a day); 4) protecting the patients (e.g. from light in porphyria); and 5) treatment by substances (giving coagulation factor VIII in hemophilia and thyroid hormones in hypothyroidism). There is a dilemma in subjecting patients to a diagnosis of progression to Huntington's chorea 20 years in advance or informing them about the high risk of hereditary disease for the next child (25% for the recessive and 50% for the dominant mode). Ethical committees have usually opted for a recommendation of selective abortion in clear-cut cases. Increasingly refined diagnostic methods have magnified the responsibility of the biochemist.
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PMID:[Prenatal diagnosis: a chance? risk? dilemma?]. 209 55

5-Aminolevulinic acid (ALA), a heme precursor overproduced in various porphyric disorders, has been implicated in iron-mediated oxidative damage to biomolecules and cell structures. From previous observations of ferritin iron release by ALA, we investigated the ability of ALA to cause oxidative damage to ferritin apoprotein. Incubation of horse spleen ferritin (HoSF) with ALA caused alterations in the ferritin circular dichroism spectrum (loss of a alpha-helix content) and altered electrophoretic behavior. Incubation of human liver, spleen, and heart ferritins with ALA substantially decreased antibody recognition (51, 60, and 28% for liver, spleen, and heart, respectively). Incubation of apoferritin with 1-10mM ALA produced dose-dependent decreases in tryptophan fluorescence (11-35% after 5h), and a partial depletion of protein thiols (18% after 24h) despite substantial removal of catalytic iron. The loss of tryptophan fluorescence was inhibited 35% by 50mM mannitol, suggesting participation of hydroxyl radicals. The damage to apoferritin had no effect on ferroxidase activity, but produced a 61% decrease in iron uptake ability. The results suggest a local autocatalytic interaction among ALA, ferritin, and oxygen, catalyzed by endogenous iron and phosphate, that causes site-specific damage to the ferritin protein and impaired iron sequestration. These data together with previous findings that ALA overload causes iron mobilization in brain and liver of rats may help explain organ-specific toxicities and carcinogenicity of ALA in experimental animals and patients with porphyria.
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PMID:Oxidative damage to ferritin by 5-aminolevulinic acid. 1250 2

Amino metabolites with potential prooxidant properties, particularly alpha-aminocarbonyls, are the focus of this review. Among them we emphasize 5-aminolevulinic acid (a heme precursor formed from succinyl-CoA and glycine), aminoacetone (a threonine and glycine metabolite), and hexosamines and hexosimines, formed by Schiff condensation of hexoses with basic amino acid residues of proteins. All these metabolites were shown, in vitro, to undergo enolization and subsequent aerobic oxidation, yielding oxyradicals and highly cyto- and genotoxic alpha-oxoaldehydes. Their metabolic roles in health and disease are examined here and compared in humans and experimental animals, including rats, quail, and octopus. In the past two decades, we have concentrated on two endogenous alpha-aminoketones: (i) 5-aminolevulinic acid (ALA), accumulated in acquired (e.g., lead poisoning) and inborn (e.g., intermittent acute porphyria) porphyric disorders, and (ii) aminoacetone (AA), putatively overproduced in diabetes mellitus and cri-du-chat syndrome. ALA and AA have been implicated as contributing sources of oxyradicals and oxidative stress in these diseases. The end product of ALA oxidation, 4,5-dioxovaleric acid (DOVA), is able to alkylate DNA guanine moieties, promote protein cross-linking, and damage GABAergic receptors of rat brain synaptosome preparations. In turn, methylglyoxal (MG), the end product of AA oxidation, is also highly cytotoxic and able to release iron from ferritin and copper from ceruloplasmin, and to aggregate proteins. This review covers chemical and biochemical aspects of these alpha-aminoketones and their putative roles in the oxidative stress associated with porphyrias, tyrosinosis, diabetes, and cri-du-chat. In addition, we comment briefly on a side prooxidant behaviour of hexosamines, that are known to constitute building blocks of several glycoproteins and to be involved in Schiff base-mediated enzymatic reactions.
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PMID:The dual face of endogenous alpha-aminoketones: pro-oxidizing metabolic weapons. 1692 Apr 3