Inborn errors of molybdenum metabolism: combined deficiencies of sulfite oxidase and xanthine dehydrogenase in a patient lacking the molybdenum cofactor.

Johnson, Jean L.; Waud, William R.; Rajagopalan, K.V.; Durán, Marinus; Beemer, Frits A.; Wadman, S.K.

doi:10.1073/pnas.77.6.3715

Cited by 155 publications

(97 citation statements)

References 27 publications

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“…MoCD is a rare inherited metabolic disorder (Johnson et al 1980;Johnson and Duran 2001) caused by defects in the biosynthesis of the molybdenum cofactor (Moco) leading to the simultaneous loss of activities of all molybdenumdependent enzymes: sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase and mitochondrial amidoximereducing component (mARC) (Schwarz et al 2009). Affected patients exhibit severe neurological abnormalities, such as microcephaly, seizures, and usually die in early childhood (Johnson and Duran 2001).…”

Section: Introductionmentioning

confidence: 99%

Molybdenum Cofactor Deficiency: A New HPLC Method for Fast Quantification of S-Sulfocysteine in Urine and Serum

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Molybdenum Cofactor Deficiency: A New HPLC Method for Fast Quantification of S-Sulfocysteine in Urine and Serum

et al. 2011

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“…Loss of Moco results in the pleiotropic loss of all molybdenum enzymes. Human Moco deficiency is a severe hereditary metabolic disorder (6), and affected patients die in early childhood.…”

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confidence: 99%

Function and Structure of the Molybdenum Cofactor Carrier Protein from Chlamydomonas reinhardtii

Fischer

Llamas

Tejada‐Jiménez

et al. 2006

Journal of Biological Chemistry

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The molybdenum cofactor (Moco) forms the catalytic site in all eukaryotic molybdenum enzymes and is synthesized by a multistep biosynthetic pathway. The mechanism of transfer, storage, and insertion of Moco into the appropriate apo-enzyme is poorly understood. In Chlamydomonas reinhardtii, a Moco carrier protein (MCP) has been identified and characterized recently. Here we show biochemical evidence that MCP binds Moco as well as the tungstate-substituted form of the cofactor (Wco) with high affinity, whereas molybdopterin, the ultimate cofactor precursor, is not bound. This binding selectivity points to a specific metal-mediated interaction with MCP, which protects Moco and Wco from oxidation with t1 ⁄ 2 of 24 and 96 h, respectively. UV-visible spectroscopy showed defined absorption bands at 393, 470, and 570 nm pointing to ene-diothiolate and protein side-chain charge transfer bonds with molybdenum. We have determined the crystal structure of MCP at 1.6 Å resolution using seleno-methionated and native protein. The monomer constitutes a Rossmann fold with two homodimers forming a symmetrical tetramer in solution. Based on conserved surface residues, charge distribution, shape, in silico docking studies, structural comparisons, and identification of an anionbinding site, a prominent surface depression was proposed as a Moco-binding site, which was confirmed by structure-guided mutagenesis coupled to substrate binding studies.Molybdenum is used in the active center of all molybdenum enzymes (1), catalyzing key metabolic reactions in the global sulfur, nitrogen, and carbon cycles in organisms ranging from bacteria to human. With the exception of nitrogenase, in all molybdenum enzymes, molybdenum is found as molybdenum cofactor (Moco) 3 (2) that consists of molybdenum covalently bound to the dithiolate moiety of a tricyclic pterin referred to as molybdopterin or metal-binding pterin (MPT), whose structure is conserved in eukaryotes, eubacteria, and archaea (3). This pterin molecule is also responsible for metal chelation in all tungsten-containing enzymes analyzed so far. Molybdenum enzymes are essential for diverse metabolic processes such as nitrate assimilation in autotrophs and phytohormone synthesis in plants (4) or sulfur detoxification and purine catabolism in mammals (5). Loss of Moco results in the pleiotropic loss of all molybdenum enzymes. Human Moco deficiency is a severe hereditary metabolic disorder (6), and affected patients die in early childhood.In all organisms studied so far, Moco is synthesized by a conserved pathway that can be divided into four major steps (3), according to the biosynthetic intermediates cyclic pyranopterin monophosphate, (formerly described as precursor Z) (7), MPT, and adenylated MPT. In the final and most diverse step of Moco biosynthesis, a single molybdenum atom is ligated to one (in pro-and eukaryotes) or two MPT dithiolates (in prokaryotes).After completion of biosynthesis, mature cofactor has to be inserted into molybdenum enzymes. In prokaryotes, a complex of proteins ...

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“…This same stereoselectivity is observed for BP-7,8-diol epoxidation occurring either during (bi)sulfite autoxidation or when treated with peroxomonosulfate. For (bi)sulfite metal-catalyzed autoxidation to yield Humans are exposed to significant levels of (bi)sulfite in addition to those present naturally as a catabolite of sulfurcontaining amino acids (19). (Bi)sulfite itself is added to a variety of foods, beverages, and drugs as a preservative and is formed in the lung by the hydration of sulfur dioxide, a ubiquitous air pollutant (3,20).…”

Section: Discussionmentioning

confidence: 99%

Epoxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene during (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen.

Reed¹,

Curtis²,

Mottley³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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The (bi)sulfite ion undergoes extensive autoxidation in neutral aqueous media with the formation of sulfur trioxide radical anion that is detected by ESR. The radical anion subsequently reacts with molecular oxygen to form a peroxyl radical. We find that when (±)-trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene is included in this autoxidation system, BP-7,8-diol is converted to diolepoxides, ultimate carcinogenic derivatives of benzo [a]pyrene. This epoxidation occurs with a stereoselectivity consistent with either a peroxyl radical or a peracid as the epoxidizing agent. The epoxidation is dependent on the concentration of both (bi)sulfite and oxygen. In the presence of 10 IAM butylated hydroxyanisole, which abolishes (bi)sulflte autoxidation, no (bi)sulfite-dependent epoxidation occurs. These results are discussed in regard to the mechanism of (bi)sulfite autoxidation, and in relationship to the cocarcinogenicity of sulfur dioxide [anhydrous (bi)sulfite] for benzo [a]pyrene-induced pulmonary neoplasia.Sulfur dioxide, an environmental pollutant, exists primarily as the (bi)sulfite anion in aqueous solution at near neutral pH. The metal-catalyzed autoxidation of the (bi)sulfite anion, studied for decades, is an oxygen-consuming chain reaction (1-3). The initiating one-electron oxidation yields the sulfur trioxide radical anion ('SO-), a predominantly sulfur-centered radical (4) that reacts with molecular oxygen. Superoxide initiates (bi)sulfite oxidation by forming 'SO (1, 5) but is not a chain propagator (2, 5), implying superoxide is not formed by reactions of the '0j radical. Presumably the reaction product of SO with oxygen is a peroxyl free radical.S53 + 02 -03SOO. [1] Huie and Neta (6) presented a kinetic argument favoring this oxygen addition reaction. Since this pathway produces a peroxyl free radical, we sought to obtain chemical support for the formation of -03SOO during (bi)sulfite autoxidation based on products of a specific trapping reaction.The trapping agent employed was (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene . This compound is stereoselectively epoxidized to form (+)-7r,8t-dihydroxy-9t, 10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) by either peroxyl radicals (7-10) or peracids (11)(12)(13). The inclusion of BP-7,8-diol in an aqueous system for (bi)sulfite autoxidation did indeed lead to the production of anti-BPDE. In this paper we present a characterization of this epoxidation and consider the implications ofthis reaction in regard to the mechanism of (bi)sulfite autoxidation and the Butylated hydroxyanisole (BHA), 5,5-dimethyl-1-pyrroline N-oxide (DMPO), superoxide dismutase, and diethylenetriaminepentaacetic acid (DETAPAC) were from Sigma. Potassium peroxomonosulfate (OXONE, DuPont) was obtained from Aldrich. Polyoxyethylene sorbitan monolaurate (Tween 20) and all chromatography solvents were from Fisher.Reaction Conditions. Tritiated and unlabeled BP-7,8-diol, in ethanol, were added to the reaction vessel, and the solvent was evaporated under a stream of N2. The r...

show abstract

Inborn errors of molybdenum metabolism: combined deficiencies of sulfite oxidase and xanthine dehydrogenase in a patient lacking the molybdenum cofactor.

Cited by 155 publications

References 27 publications

Molybdenum Cofactor Deficiency: A New HPLC Method for Fast Quantification of S-Sulfocysteine in Urine and Serum

Molybdenum Cofactor Deficiency: A New HPLC Method for Fast Quantification of S-Sulfocysteine in Urine and Serum

Function and Structure of the Molybdenum Cofactor Carrier Protein from Chlamydomonas reinhardtii

Epoxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene during (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen.

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