Molybdenum Cofactor Deficiency in Humans
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Abstract:
Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic–ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of MOCS1, MOCS2, MOCS3, and GPHN. Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.Keywords:
Molybdenum Cofactor
Molybdenum Cofactor
Aldehyde oxidase
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Molybdenum Cofactor
Xanthine dehydrogenase
Hypoxanthine
Pterin
Xanthine
Sulfite oxidase
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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Molybdenum and tungsten are available to all organisms, with molybdenum having the far greater abundance and availability. Molybdenum occurs in a wide range of metalloenzymes in bacteria, fungi, algae, plants and animals, while tungsten was found to be essential only for a limited range of bacteria. In order to gain biological activity, molybdenum has to be complexed by a pterin compound, thus forming a molybdenum cofactor. In this article I will review the way that molybdenum takes from uptake into the cell, via formation of the molybdenum cofactor and its storage, to the final modification of molybdenum cofactor and its insertion into apo-metalloenzymes.
Molybdenum Cofactor
Pterin
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We examined molybdenum cofactor activity in chlorate-resistant (chl) and nitrate reductase-deficient (nar) insertion mutants and wild-type strains of Escherichia coli K-12. The bacterial molybdenum cofactor was assayed by its ability to restore activity to the cofactor-deficient nitrate reductase found in the nit-1 strain of Neurospora crassa. In the wild-type E. coli strains, molybdenum cofactor was synthesized constitutively and found in both cytoplasmic and membrane fractions. Cofactor was found in two forms: the demolybdo form required additional molybdate in the assay mix for detection, whereas the molybdenum-containing form was active without additional molybdate. The chlA and chlE mutants had no detectable cofactor. The chlB and the narG, narI, narK, and narL (previously designated chlC) strains had cofactor levels similar to those of the wild-type strains, except the chlB strains had two to threefold more membrane-bound cofactor. Cofactor levels in the chlD and chlG strains were sensitive to molybdate. When grown in 1 microM molybdate, the chlD strains had only 15 to 20% of the wild-type levels of the demolybdo and molybdenum-containing forms of the cofactor. In contrast, the chlG strains had near wild-type levels of demolybdo cofactor when grown in 1 microM molybdate, but none of the molybdenum-containing form of the cofactor. Near wild-type levels of both forms of the cofactor were restored to the chlD and chlG strains by growth in 1 mM molybdate.
Molybdenum Cofactor
Sodium molybdate
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Experiments were performed to determine whether defects in molybdenum cofactor metabolism were responsible for the pleiotropic loss of the molybdoenzymes nitrate reductase and formate dehydrogenase in chl mutants of Escherichia coli. In wild-type E. coli, molybdenum cofactor activity was present in both the soluble and membrane-associated fractions when the cells were grown either aerobically or anaerobically, with and without nitrate. Molybdenum cofactor in the soluble fraction decreased when the membrane-bound nitrate reductase and formate dehydrogenase were induced. In the chl mutants, molybdenum cofactor activity was found in the soluble fraction of chlA, chlB, chlC, chlD, chlE, and chlG, but only chlB, chlC, chlD, and chlG expressed cofactor activity in the membrane fraction. The defect in the chlA mutants which prevented incorporation of the soluble cofactor into the membrane also caused the soluble cofactor to be defective in its ability to bind molybdenum. This cofactor was not active in the absence of molybdate, and it required at least threefold more molybdate than did the wild type in the Neurospora crassa nit-1 complementation assay. However, the cofactor from the chlA strain mediated the dimerization of the nit-1 subunits in the presence and absence of molybdate to yield the 7.9S dimer. Growth of chlA mutants in medium with increased molybdate did not repair the defect in the chlA cofactor nor restore the molybdoenzyme activities. Thus, molybdenum cofactor was synthesized in all the chl mutants, but additional processing steps may be missing in chlA and chlE mutants for proper insertion of cofactor in the membrane.
Molybdenum Cofactor
Formate dehydrogenase
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The maturation of Escherichia coli nitrate reductase A requires the incorporation of the Mo-(bis-MGD) cofactor to the apoprotein. For this process, the NarJ chaperone is strictly required. We report the first description of protein interactions between molybdenum cofactor biosynthetic proteins (MogA, MoeA, MobA, and MobB) and the aponitrate reductase (NarG) using a bacterial two-hybrid approach. Two conditions have to be satisfied to allow the visualization of the interactions, (i) the presence of an active and mature molybdenum cofactor and (ii) the presence of the NarJ chaperone and of the NarG structural partner subunit, NarH. Formation of tungsten-substituted cofactor prevents the interaction between NarG and the four biosynthetic proteins. Our results suggested that the final stages of molybdenum cofactor biosynthesis occur on a complex made up by MogA, MoeA, MobA, and MobB, which is also in charge with the delivery of the mature cofactor onto the aponitrate reductase A in a NarJ-assisted process.
Molybdenum Cofactor
Chaperone (clinical)
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The oxidoreductase YdhV in Escherichia coli has been predicted to belong to the family of molybdenum/tungsten cofactor (Moco/Wco)-containing enzymes. In this study, we characterized the YdhV protein in detail, which shares amino acid sequence homology with a tungsten-containing benzoyl-CoA reductase binding the bis-W-MPT (for metal-binding pterin) cofactor. The cofactor was identified to be of a bis-Mo-MPT type with no guanine nucleotides present, which represents a form of Moco that has not been found previously in any molybdoenzyme. Our studies showed that YdhV has a preference for bis-Mo-MPT over bis-W-MPT to be inserted into the enzyme. In-depth characterization of YdhV by X-ray absorption and electron paramagnetic resonance spectroscopies revealed that the bis-Mo-MPT cofactor in YdhV is redox active. The bis-Mo-MPT and bis-W-MPT cofactors include metal centers that bind the four sulfurs from the two dithiolene groups in addition to a cysteine and likely a sulfido ligand. The unexpected presence of a bis-Mo-MPT cofactor opens an additional route for cofactor biosynthesis in E. coli and expands the canon of the structurally highly versatile molybdenum and tungsten cofactors.
Molybdenum Cofactor
Pterin
Metalloprotein
Flavin adenine dinucleotide
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Molybdenum Cofactor
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Molybdenum Cofactor
Aldehyde oxidase
Xanthine dehydrogenase
Pterin
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