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591.
Zinc binding to peptide analogs of the structural zinc site in alcohol dehydrogenase: Implications for an entatic state 总被引:1,自引:0,他引:1
Bergman T Zhang K Palmberg C Jörnvall H Auld DS 《Cellular and molecular life sciences : CMLS》2008,65(24):4019-4027
Zinc binding to the peptide replica and analogs to residues 93–115 of horse liver alcohol dehydrogenase (ADH) was examined
by competition of the peptides and the chromophoric chelator 4-(2- pyridylazo)resorcinol for zinc and X-ray absorption fine
structure analysis of the zinc ligands. In the enzyme, zinc is coordinated by four Cys residues. In the peptide replica, zinc
is bound to three Cys and one His residue. A four-Cys zinc coordination is observed only when His is removed, leading to increased
zinc stability. ADH crystal structures reveal that the ε-amino group of the conserved residue Lys323 is within H-bond distance
of the backbone amide oxygens of residues 103, 105 and 108, likely stabilizing the zinc coordination in the enzyme. The peptide
data thus indicate structural strain and increased energy in the zinc-binding site in the protein, characteristic of an entatic
state, implying a functional nature for this zinc site.
Received 3 July 2008; received after revision 11 August 2008; accepted 1 September 2008 相似文献
592.
Cardiolipin, the heart of mitochondrial metabolism 总被引:5,自引:0,他引:5
Cardiolipin is a unique phospholipid, which is almost exclusively localized in the mitochondrial inner membrane where it is
synthesized from phosphatidylglycerol and cytidinediphosphate-diacylglycerol. After primary synthesis, the mature acyl chain
composition of cardiolipin is achieved by at least two remodeling mechanisms. In the mitochondrial membrane cardiolipin plays
an important role in energy metabolism, mainly by providing stability for the individual enzymes and enzyme complexes involved
in energy production. Moreover, cardiolipin is involved in different stages of the mitochondrial apoptotic process and in
mitochondrial membrane dynamics. Cardiolipin alterations have been described in various pathological conditions. Patients
suffering from Barth syndrome have an altered cardiolipin homeostasis caused by a primary deficiency in cardiolipin remodeling.
Alterations in cardiolipin content or composition have also been reported in more frequent diseases such as diabetes and heart
failure. In this review we provide an overview of cardiolipin metabolism, function and its role in different pathological
states.
Received 16 January 2008; received after revision 26 February 2008; accepted 26 March 2008 相似文献
593.
594.
Twigger SN Pruitt KD Fernández-Suárez XM Karolchik D Worley KC Maglott DR Brown G Weinstock G Gibbs RA Kent J Birney E Jacob HJ 《Nature genetics》2008,40(5):523-527
It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database. 相似文献
595.
Vermulst M Wanagat J Kujoth GC Bielas JH Rabinovitch PS Prolla TA Loeb LA 《Nature genetics》2008,40(4):392-394
Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis. 相似文献
596.
Vitart V Rudan I Hayward C Gray NK Floyd J Palmer CN Knott SA Kolcic I Polasek O Graessler J Wilson JF Marinaki A Riches PL Shu X Janicijevic B Smolej-Narancic N Gorgoni B Morgan J Campbell S Biloglav Z Barac-Lauc L Pericic M Klaric IM Zgaga L Skaric-Juric T Wild SH Richardson WA Hohenstein P Kimber CH Tenesa A Donnelly LA Fairbanks LD Aringer M McKeigue PM Ralston SH Morris AD Rudan P Hastie ND Campbell H Wright AF 《Nature genetics》2008,40(4):437-442
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes. 相似文献
597.
Döring A Gieger C Mehta D Gohlke H Prokisch H Coassin S Fischer G Henke K Klopp N Kronenberg F Paulweber B Pfeufer A Rosskopf D Völzke H Illig T Meitinger T Wichmann HE Meisinger C 《Nature genetics》2008,40(4):430-436
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women. 相似文献
598.
Colleen McBride and colleagues argue that progress on a multifaceted research agenda is necessary to reap the full benefits and avoid the potential pitfalls of the emerging area of personalized genomics. They also outline one element of this agenda, the Multiplex Initiative, which has been underway since 2006. 相似文献
599.
600.
SNP genotyping has emerged as a technology to incorporate copy number variants (CNVs) into genetic analyses of human traits. However, the extent to which SNP platforms accurately capture CNVs remains unclear. Using independent, sequence-based CNV maps, we find that commonly used SNP platforms have limited or no probe coverage for a large fraction of CNVs. Despite this, in 9 samples we inferred 368 CNVs using Illumina SNP genotyping data and experimentally validated over two-thirds of these. We also developed a method (SNP-Conditional Mixture Modeling, SCIMM) to robustly genotype deletions using as few as two SNP probes. We find that HapMap SNPs are strongly correlated with 82% of common deletions, but the newest SNP platforms effectively tag about 50%. We conclude that currently available genome-wide SNP assays can capture CNVs accurately, but improvements in array designs, particularly in duplicated sequences, are necessary to facilitate more comprehensive analyses of genomic variation. 相似文献