Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.
GA (glucoamylase) hydrolyses starch and polysaccharides to beta-D-glucose. RoGA (Rhizopus oryzae GA) consists of two functional domains, an N-terminal SBD (starch-binding domain) and a C-terminal catalytic domain, which are connected by an O-glycosylated linker. In the present study, the crystal structures of the SBD from RoGA (RoGACBM21) and the complexes with beta-cyclodextrin (SBD-betaCD) and maltoheptaose (SBD-G7) were determined. Two carbohydrate binding sites, I (Trp(47)) and II (Tyr(32)), were resolved and their binding was co-operative. Besides the hydrophobic interaction, two unique polyN loops comprising consecutive asparagine residues also participate in the sugar binding. A conformational change in Tyr(32) was observed between unliganded and liganded SBDs. To elucidate the mechanism of polysaccharide binding, a number of mutants were constructed and characterized by a quantitative binding isotherm and Scatchard analysis. A possible binding path for long-chain polysaccharides in RoGACBM21 was proposed.
Malic enzymes are widely distributed in nature, and have important biological functions. , and oxalate. This represents the first structural information on an NADP + -dependent malic enzyme. Despite the sequence conservation, there are large differences in several regions of the pigeon enzyme structure compared to the human enzyme. One region of such differences is at the binding site for the 2Ј-phosphate group of the NADP + cofactor, which helps define the cofactor selectivity of the enzymes. Specifically, the structural information suggests Lys362 may have an important role in the NADP + selectivity of the pigeon enzyme, confirming our earlier kinetic observations on the K362A mutant. Our structural studies also revealed differences in the organization of the tetramer between the pigeon and the human enzymes, although the pigeon enzyme still obeys 222 symmetry. Malic enzymes are generally homo-tetramers of 60 kD monomers. The conversion of malate to pyruvate by these enzymes generally proceeds in two steps: oxidation (dehydrogenation) of malate to produce oxaloacetate, and then decarboxylation of oxaloacetate to produce pyruvate and Keywords
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