Biomedical subjects

J Leiper

Publications and source records attributed to J Leiper.

11 recordsLinked to original sources

PubMed2001

Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase.

Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 2.1.4.1) and arginine deiminase (EC 3.5.3.6), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys-His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA-DDAH and arginine-amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings.

Amidohydrolases↗

PubMed2000

Stay on Your Feet Safety Walks Group.

The Safety Walks Group is an initiative that evolved from the Stay on Your Feet Program. The strategies used in this program target both behavioural and environmental change and are based on the five areas for action under the Ottawa Charter (WHO, 1986) and Jakarta Declaration (WHO, 1997). The Safety Walks Group addresses the issue of public hazards via the use of a standard checklist covering pedestrian areas, business houses and accommodation. The project provided a forum for seniors to be proactive, working with the authorities to address the issue of public hazards and make the environment safer.

Accidental Falls↗

PubMed1999

Biological significance of endogenous methylarginines that inhibit nitric oxide synthases.

The guanidino-methylated arginine analogue NG monomethyl-L-arginine (L-NMMA) has been the standard nitric oxide synthase inhibitor used to evaluate the role of the L-arginine:nitric oxide pathway. However, L-NMMA and other methylated arginine residues are also synthesised in vivo by the action of a family of enzymes known as protein arginine methyltransferases. Proteolysis of proteins containing methylated arginine residues releases free methylarginine residues into the cytosol from where they may pass out of the cell into plasma. Of the three known methylarginine residues produced in mammals only asymmetrically methylated forms (L-NMMA and asymmetric dimethylarginine (ADMA)) but not symmetrically methylated arginine (symmetric dimethylarginine (SDMA)) inhibit nitric oxide synthase (NOS). We and others have proposed that endogenously produced asymmetrically methylated arginines may modulate NO production and that the accumulation of these residues in disease states may contribute to pathology. The activity of the enzyme dimethylarginine dimethylaminohydrolase that metabolises asymmetric methylarginines may be of critical importance in affecting NO pathways in health or disease.

Amidohydrolases↗

PubMed1999

Regulation of transforming growth factor-beta, basic fibroblast growth factor, and vascular endothelial cell growth factor mRNA in peripheral blood leukocytes in patients with diabetic retinopathy.

In the present study, we examined the effect of glucose concentration on the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-beta) mRNA using reverse transcriptase-polymerase chain reaction (RT-betaCR) in normal healthy leukocytes in vitro and in leukocytes from patients with type 1 diabetes mellitus. In vitro, the level of TGF-beta mRNA was altered in response to the glucose concentration (maximum at 10 mmol/L), while bFGF mRNA remained relatively constant and VEGF mRNA varied with no clear correlation with the glucose concentration. Leukocytes from type 1 patients showed no difference in bFGF or TGF-beta mRNA levels compared with age-matched healthy controls. However, VEGF mRNA was significantly lower in type 1 patients compared with controls (P < .05). When the patients were subtyped according to the severity of retinopathy, the level of TGF-beta mRNA was elevated selectively in patients with evidence of active new retinal vessels (P < .01) and VEGF121 mRNA was reduced in patients with mild to moderate retinopathy. Thus, leukocyte growth factor mRNAs respond to acute changes in the glucose concentration in vitro, and are differentially expressed in type 1 diabetic patients during the course of the disease.

Adult↗

PubMed1999