Molecular chaperones and proteases monitor the folded state of other proteins. In addition to recognizing non-native conformations, these quality control factors distinguish substrates that can be refolded from those that need to be degraded. To investigate the molecular basis of this process, we have solved the crystal structure of DegP (also known as HtrA), a widely conserved heat shock protein that combines refolding and proteolytic activities. The DegP hexamer is formed by staggered association of trimeric rings. The proteolytic sites are located in a central cavity that is only accessible laterally. The mobile side-walls are constructed by twelve PDZ domains, which mediate the opening and closing of the particle and probably the initial binding of substrate. The inner cavity is lined by several hydrophobic patches that may act as docking sites for unfolded polypeptides. In the chaperone conformation, the protease domain of DegP exists in an inactive state, in which substrate binding in addition to catalysis is abolished.
The aim of this study was to stratify risk for postpartum diabetes in women who have gestational diabetes. Women with gestational diabetes were recruited between 1989 and 1999, and 302 were followed with oral glucose tolerance tests at 9 months and 2, 5, 8, and 11 years postpregnancy. The 8-year postpartum diabetes risk was 52.7% (130 diabetic cases). Risk was increased in women with autoantibodies to GAD and/or insulinoma antigen-2 (adjusted hazard ratio 4.1; P < 0.0001), women who required insulin during pregnancy (4.7; P < 0.0001), women with BMI >30 kg/m 2 (1.5; P ؍ 0.04), and women with more than two prior pregnancies (2.5; P ؍ 0.02). Women without these risk factors had a postpartum diabetes risk of 14% by 8 years, and risk rose incrementally to 96% by 8 years in autoantibody-positive women. Parity status, C-reactive protein concentration, a diabetes family history, maternal age, weeks of gestation, and the child's birth weight did not significantly affect risk in multivariate analysis. Prospective diabetes assessment is indicated and intervention should be considered in women with gestational diabetes who are autoantibody positive, require insulin treatment during pregnancy, or are obese. Diabetes 55:792-797, 2006 G estational diabetes mellitus (GDM) complicates ϳ4% of pregnancies and is defined as glucose intolerance with onset or first diagnosis during pregnancy (1). GDM substantially increases the risk to develop postpartum diabetes and thus identifies a high-risk population for the development of both type 1 and type 2 diabetes. Risk estimates of type 2 diabetes after GDM vary from 17 to 63% within 5-16 years after pregnancy, depending upon the ethnic background of the study population and the detection method for GDM and glucose intolerance (2-4). Like type 2 diabetes, the incidence of postpartum diabetes appears to be increasing (5). Reported risk factors for postpartum diabetes include the detection of islet autoantibodies (6,7), insulin treatment during pregnancy, BMI, and age at delivery (3).The German GDM study has prospectively followed patients with GDM for up to 11 years for the purpose of estimating diabetes risk and identifying factors that modify risk. Here we report diabetes risk with respect to anthropometric markers such as BMI, insulin requirement during pregnancy, family history of diabetes, the number of previous pregnancies, age at delivery, duration of gestation, or birth weight of child and serological markers such as the presence of islet autoantibodies and serum concentrations of C-reactive protein (CRP) in this cohort. RESEARCH DESIGN AND METHODSThe German GDM prospective study follows women with GDM from delivery (6,8). Between 1989 and 1999, 302 patients with GDM were recruited from hospitals in Germany and participated in at least one follow-up contact after delivery. GDM was diagnosed following the criteria of the German Diabetes Association using an oral glucose tolerance test (OGTT) with 75-g glucose load. Women were considered to have GDM if two of three capillary bl...
The crystal structure of recombinant human GTP cyclohydrolase I was solved by Patterson search methods by using the coordinates of the Escherichia coli enzyme as a model. The human as well as bacterial enzyme were shown to contain an essential zinc ion coordinated to a His side chain and two thiol groups in each active site of the homodecameric enzymes that had escaped detection during earlier studies of the E. coli enzyme. The zinc ion is proposed to generate a hydroxyl nucleophile for attack of imidazole ring carbon atom eight of the substrate, GTP. It may also be involved in the hydrolytic release of formate from the intermediate, 2-amino-5-formylamino-6-ribosylamino-4(3H)-pyrimidinone 5-triphosphate, and in the consecutive Amadori rearrangement of the ribosyl moiety.
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