Insights on the conformation and appropriate drug-target sites on retinal IMPDH1 using the 604-aa isoform lacking the C-terminal extension

Background and purpose: Retinitis pigmentosa (RP) accounts for 2 percent of global cases of blindness. The RP10 form of the disease results from mutations in isoform 1 of inosine 5'-monophosphate dehydrogenase (IMPDH1), the rate-limiting enzyme in the de novo purine nucleotide synthesis pathway. Retinal photoreceptors contain specific isoforms of IMPDH1 characterized by terminal extensions. Considering previously reported significantly varied kinetics among retinal isoforms, the current research aimed to investigate possible structural explanations and suitable functional sites for the pharmaceutical targeting of IMPDH1 in RP. Experimental approach: A recombinant 604-aa IMPDH1 isoform lacking the carboxyl-terminal peptide was produced and underwent proteolytic digestion with α-chymotrypsin. Dimer models of wild type and engineered 604-aa isoform were subjected to molecular dynamics simulation. Findings/Results: The IMPDH1 retinal isoform lacking C-terminal peptide was shown to tend to have more rapid proteolysis (~16% digestion in the first two minutes). Our computational data predicted the potential of the amino-terminal peptide to induce spontaneous inhibition of IMPDH1 by forming a novel helix in a GTP binding site. On the other hand, the C-terminal peptide might block the probable inhibitory role of the N-terminal extension. Conclusion and implications: According to the findings, augmenting IMPDH1 activity by suppressing its filamentation is suggested as a suitable strategy to compensate for its disrupted activity in RP. This needs specific small molecule inhibitors to target the filament assembly interface of the enzyme

Human parvovirus B19 in Iranian pregnant women: A serologic survey

Background: Parvovirus B19 infection is associated with clinical symptoms that vary in the spectrum from trivial to severe. The important clinical manifestations are erythema infectiosum or the fifth disease, transient aplastic anemia in patients with hemoglobinopathies, acute polyarthralgia syndrome in adults, hydrops fetalis, spontaneous abortion and stillbirth. Acute infection in nonimmune pregnant women can lead to fetal hydrops. In view of the many complications that can result from acute parvovirus B19 infections during pregnancy, documenting the seroprevalence of anti-parvovirus B19 IgG and its association with the history of abortion in an Iranian population of pregnant women would be of value. Materials and Methods: Serum samples from 86 pregnant women were collected between May and September 2011 in West Azerbaijan province of Iran. Every pregnant woman completed a questionnaire which included age, history of tattooing, blood transfusion, and abortion. Anti-B19 specific IgG was detected by using commercial enzyme-linked immunosorbent assays. Results: Anti-B19-specific IgG antibody was detected in (65/86, 75.6%) of pregnant women. The mean age was 25.56 ± 5.30 years and three women had a documented history of blood transfusion (2 of them tested seropositive for B19). 16/18 (88.8%) of women with a history of abortion were IgG positive. The frequency of abortion sessions in the seropositive group (25 sessions of abortion: 11 women experienced once, 2 twice, 2 thrice and one 4 times) was 4.03 times greater than abortion in seronegative group (2 abortions/21 seronegative women). Conclusion: Our study reaffirms previous reports regarding the higher frequency of abortion among anti-B19 IgG seropositive pregnant women and a possible role of this viral infection in the pathogenesis of abortion