Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Menkes (MNK) protein is a vital component of copper homeostasis in mammalian cells. In this paper we provide the first biochemical evidence that the MNK protein functions as a copper-translocating P-type ATPase in mammalian cells. The enzyme activity in membrane vesicles prepared from Chinese hamster ovary cells overexpressing MNK was ATP-dependent, correlated with the amount of MNK and followed Michaelis-Menten kinetics with respect to copper. The copper transport was observed only under reducing conditions suggesting MNK transports Cu(I). This study opens the way to detailed structure-function studies and assessment of functional MNK derived from patients with Menkes disease.
FEBS Lett 1998 Sep 18
PMID:ATP-dependent copper transport by the Menkes protein in membrane vesicles isolated from cultured Chinese hamster ovary cells. 976 3

A girl with a 46,X,t(X;21) (q13.3;p11.1) karyotype presented with skin redundancy, especially in the neck, prominent occiput and micrognathia, and later developed hypotonia, hypopigmentation, sparse scalp hair, and profound mental retardation characteristic of Menkes disease. Her serum copper (14 microg/dl) and ceruloplasmin (9 mg/dl) levels were extremely low. Fluorescent in situ hybridization analysis with a 100-kb P1-derived artificial chromosome probe containing the Menkes disease gene demonstrated three twin-signals, one on the normal X chromosome and one each on derivative chromosomes X and 21, indicating that the Xq13.3 breakpoint was located within the gene. Replication pattern analysis showed that the normal X chromosome was late replicating, whereas the derivative X chromosome was selectively early replicating. These results indicated that Menkes disease in our patient resulted from a de novo translocation that disrupts the disease gene.
Am J Med Genet 1998 Sep 23
PMID:Translocation t(X;21)(q13.3; p11.1) in a girl with Menkes disease. 978 59

The cDNA, coding for the first metal-binding domain (MBD1) of Menkes protein, was cloned into the T7-system based vector, pCA. The T7 lysozyme-encoding plasmid, pLysS, is shown to be crucial for expression, suggesting that the protein is toxic to the cells. Adding copper to the growth medium did not affect the plasmid stability. MBD1 is purified in two steps with a typical yield of 12 mg.L-1. Menkes protein, a P-type ATPase, contains a sequence GMXCXSC that is repeated six times, at the N-terminus. The paired cysteine residues are involved in metal binding. MBD1 has only two cysteine residues, which can exist as free thiol groups (reduced), as a disulphide bond (oxidized) or bound to a metal ion [e.g. Cu(I)-MBD1]. These three MBD1 forms have been investigated using CD. No major spectral change was seen between the different MBD1 forms, indicating that the folding is not changed upon metal binding. A copper-bound MBD1 was also studied by EPR, and the lack of an EPR signal suggests that the oxidation state of copper bound to MBD1 is Cu(I). Cu(I) binding studies were performed by equilibrium dialysis and revealed a stoichiometry of 1 : 1 and an apparent Kd = 46 microM. Oxidized MBD1, however, is not able to bind copper. Different copper complexes were investigated for their ability to reconstitute apo-MBD1. Given the same total copper concentration CuCl43- was superior to Cu(I)-thiourea (structural analogue of metallothionein) and Cu(I)-glutathione (used at fivefold higher copper concentration) although the latter two were able to partially reconstitute apo-MBD1. Cu(II) was not able to reconstitute apo-MBD1, presumably due to Cu(II)-induced oxidation of the thiol groups. Based on our results, glutathione and/or metallothionein are likely candidates for the in vivo incorporation of copper to Menkes protein.
Eur J Biochem 1999 Sep
PMID:Expression, purification and copper-binding studies of the first metal-binding domain of Menkes protein. 1049 Nov 37

We have optimised the overexpression and purification of the N-terminal end of the Menkes disease protein expressed in Escherichia coli, containing one, two and six metal binding domains (MBD), respectively. The domain(s) have been characterised using circular dichroism (CD) and fluorescence spectroscopy, and their copper(I) binding properties have been determined. Structure prediction derived from far-UV CD indicates that the secondary structure is similar in the three proteins and dominated by beta-sheet. The tryptophan fluorescence maximum is blue-shifted in the constructs containing two and six MBDs relative to the monomer, suggesting more structurally buried tryptophan(s), compared to the single MBD construct. Copper(I) binding has been studied by equilibrium dialysis under anaerobic conditions. We show that the copper(I) binding to constructs containing two and six domains is cooperative, with Hill coefficients of 1.5 and 4, respectively. The apparent affinities are described by K(0.5), determined to be 65 microM and 19 microM for constructs containing two and six domains, respectively. Our data reveal a unique regulation of Menkes protein upon a change in copper(I) concentration. The regulation does not occur as an 'all-or-none' cooperativity, suggesting that the copper(I) binding domains have a basal low affinity for binding and release of copper(I) at low concentrations but are able to respond to higher copper levels by increasing the affinity, thereby contributing to prevent the copper concentration from reaching toxic levels in the cell.
Biochim Biophys Acta 1999 Sep 14
PMID:Cooperative binding of copper(I) to the metal binding domains in Menkes disease protein. 1055 64

Copper ion homeostasis is complicated in that copper is an essential element needed for a variety of cellular processes but is toxic at excess levels. To identify Candida albicans genes that are involved in resistance to copper ion toxicity, a library containing inserts of C. albicans genomic DNA was used to complement the copper sensitivity phenotype of a Saccharomyces cerevisiae cup1Delta strain that is unable to produce Cup1p, a metallothionein (MT) responsible for high-level copper ion resistance. A P1-type ATPase (CPx type) that is closely related to the human Menkes and Wilson disease proteins was cloned. The gene encoding this pump was termed CRD1 (for copper resistance determinant). A gene encoding a 76-amino-acid MT similar to higher eukaryotic MTs in structure was also cloned, and the gene was termed CRD2. Transcription of the CRD1 gene was found to increase upon growth with increasing copper levels, while the CRD2 mRNA was expressed at a constant level. Strains with the CRD1 gene disrupted were extremely sensitive to exogenous copper and failed to grow in medium containing 100 microM CuSO(4). These crd1 strains also exhibited increased sensitivity to silver and cadmium, indicating that Crd1p is somewhat promiscuous with respect to metal ion transport. Although strains with the CRD2 gene disrupted showed reduced growth rate with increasing copper concentration, the crd2 mutants eventually attained wild-type levels of growth, demonstrating that CRD2 is less important for resistance to copper ion toxicity. Crd1p is the first example of a eukaryotic copper pump that provides the primary source of cellular copper resistance, and its ability to confer silver resistance may enhance the prevalence of C. albicans as a nosocomial pathogen.
J Bacteriol 2000 Sep
PMID:Role of a Candida albicans P1-type ATPase in resistance to copper and silver ion toxicity. 1094 34

The Hah1 metallochaperone protein is implicated in copper delivery to the Menkes and Wilson disease proteins. Hah1 and the N-termini of its target proteins belong to a family of metal binding domains characterized by a conserved MT/HCXXC sequence motif. The crystal structure of Hah1 has been determined in the presence of Cu(I), Hg(II), and Cd(II). The 1.8 A resolution structure of CuHah1 reveals a copper ion coordinated by Cys residues from two adjacent Hah1 molecules. The CuHah1 crystal structure is the first of a copper chaperone bound to copper and provides structural support for direct metal ion exchange between conserved MT/HCXXC motifs in two domains. The structures of HgHah1 and CdHah1, determined to 1.75 A resolution, also reveal metal ion coordination by two MT/HCXXC motifs. An extended hydrogen bonding network, unique to the complex of two Hah1 molecules, stabilizes the metal binding sites and suggests specific roles for several conserved residues. Taken together, the structures provide models for intermediates in metal ion transfer and suggest a detailed molecular mechanism for protein recognition and metal ion exchange between MT/HCXXC containing domains.
Nat Struct Biol 2000 Sep
PMID:Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. 1096 47

Extracts from three human cell lines were found to contain abridged Menkes disease gene transcripts with novel insertion sequences. The transcript variant that is the focus of the present study codes for a 103-residue protein containing the first heavy-metal-binding domain (Hmb1) of ATP7A, the Cu-ATPase associated with Menkes disease. This transcript variant has a 45-bp nucleotide insert interposed between exons 1 and 2 of ATP7A that starts with a 5' ATG that is in-frame with the downstream ATG translation start site of ATP7A. We report here that the 66-bp nucleotides positioned between the upstream and downstream ATG sites encode 22 amino acid residues whose primary structure in part meets the criteria for a nuclear-localization sequence (NLS). We have referred to the transcript as nuclear Menkes-like (NML) 45. A green fluorescent protein (GFP) construct with NML45 when transfected in Chinese hamster ovary cells localized to the cell nucleus. A similar construct without the 66-bp segment exhibited a random dispersed fluorescent pattern in the cytosol. GFP constructs encoding ATP7A exons likewise failed to direct GFP into the cell nucleus, suggesting the nuclear determinant is not in an internal domain of the protein. The data suggest that the 22-residue segment contains an NLS for an 11.2-kDa protein with one Cu-binding site that may function as a chaperone to transport Cu into the nucleus of mammalian cells.
Biochem J 2000 Sep 15
PMID:Evidence for a Menkes-like protein with a nuclear targeting sequence. 1097 Aug 2

Early treatment reportedly prevents neurological disturbance in patients with Menkes disease. To promote early diagnosis, a questionnaire concerning symptoms during the neonatal period and at the age of 1 month was sent to the mothers of 14 patients with Menkes disease. The height, body weight and head circumference were almost normal in most of the Menkes patients. At the age of one month, all patients had abnormal hair. The mothers noticed it in 8 cases, and in the remaining 6 cases, the abnormalities were confirmed by the photos at the age of one month. At this age, the mothers noticed weak activity in 5, jaundice in 5, dyspnea in 4 cases, feeding disturbance in 3, hypothermia in 2 and eczema in 2. These results suggest that recognizing hair abnormalities at a one-month check-up may provide a clue to the early diagnosis of Menkes disease.
No To Hattatsu 2002 Sep
PMID:[Clinical manifestations for early diagnosis of the patient with classical Menkes disease]. 1223 49

We report a case of Menkes disease with urinary bladder hemorrhage. Diverticulums were found at 1 year and 3 months of age. He had repetitive urinary tract infections at 2 years old and died of urinary hemorrhage at 2 years and 9 months. Large hematoma and diverticulum were found at necropsy. In patients with Menkes disease, attention should paid to urinary complications.
No To Hattatsu 2002 Sep
PMID:[A case of Menkes disease with urinary bladder hemorrhage]. 1223 57

Menkes disease is a severe multisystem disorder due to defective bioavailability and transport of copper at the cellular level. Deficient activity of lysyl oxidase, a copper-dependent enzyme, causes defective collagen cross-linking leading to osteoporosis and pathological fractures in these children. The objective of the study was to evaluate the changes in bone mineral density following pamidronate treatment in children with Menkes disease. The study design was an open observational study of three children with Menkes disease and significant osteoporosis with or without pathological fractures, all of whom received pamidronate treatment for 1 year. There were 34-55% and 16-36% increases in lumbar spine bone mineral content and areal bone mineral density, respectively, following 1 year of treatment with pamidronate. There were no further fractures in two of the three children treated. No adverse effects of pamidronate treatment were noted. Pamidronate treatment was associated with an increase in bone mineral density and may be an effective treatment modality for the management of osteoporosis in children with Menkes disease.
J Inherit Metab Dis 2002 Sep
PMID:Pamidronate treatment improves bone mineral density in children with Menkes disease. 1240 89


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