Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutive biosynthesis of lipid A via the Raetz pathway is essential for the viability and fitness of Gram-negative bacteria, includingChlamydia trachomatis Although nearly all of the enzymes in the lipid A biosynthetic pathway are highly conserved across Gram-negative bacteria, the cleavage of the pyrophosphate group of UDP-2,3-diacyl-GlcN (UDP-DAGn) to form lipid X is carried out by two unrelated enzymes: LpxH in beta- and gammaproteobacteria and LpxI in alphaproteobacteria. The intracellular pathogenC. trachomatislacks an ortholog for either of these two enzymes, and yet, it synthesizes lipid A and exhibits conservation of genes encoding other lipid A enzymes. Employing a complementation screen against aC. trachomatisgenomic library using a conditional-lethallpxHmutantEscherichia colistrain, we have identified an open reading frame (Ct461, renamedlpxG) encoding a previously uncharacterized enzyme that complements the UDP-DAGn hydrolase function inE. coliand catalyzes the conversion of UDP-DAGn to lipid Xin vitro LpxG shows little sequence similarity to either LpxH or LpxI, highlighting LpxG as the founding member of a third class of UDP-DAGn hydrolases. Overexpression of LpxG results in toxic accumulation of lipid X and profoundly reduces the infectivity ofC. trachomatis, validating LpxG as the long-sought-after UDP-DAGn pyrophosphatase in this prominent human pathogen. The complementation approach presented here overcomes the lack of suitable genetic tools forC. trachomatisand should be broadly applicable for the functional characterization of other essentialC. trachomatisgenes.IMPORTANCEChlamydia trachomatisis a leading cause of infectious blindness and sexually transmitted disease. Due to the lack of robust genetic tools, the functions of manyChlamydiagenes remain uncharacterized, including the essential gene encoding the UDP-DAGn pyrophosphatase activity for the biosynthesis of lipid A, the membrane anchor of lipooligosaccharide and the predominant lipid species of the outer leaflet of the bacterial outer membrane. We designed a complementation screen against theC. trachomatisgenomic library using a conditional-lethal mutant ofE. coliand identified the missing essential gene in the lipid A biosynthetic pathway, which we designatedlpxG We show that LpxG is a member of the calcineurin-like phosphatases and displays robust UDP-DAGn pyrophosphatase activityin vitro Overexpression of LpxG inC. trachomatisleads to the accumulation of the predicted lipid intermediate and reduces bacterial infectivity, validating thein vivofunction of LpxG and highlighting the importance of regulated lipid A biosynthesis inC. trachomatis.
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PMID:Discovery of the Elusive UDP-Diacylglucosamine Hydrolase in the Lipid A Biosynthetic Pathway in Chlamydia trachomatis. 2700 61

In the era of antiretroviral therapy, people living with HIV/AIDS live longer and are subject to co-morbidities that affect the general population, such as chronic kidney disease. An increasing number of people living with HIV/AIDS with end-stage renal disease are candidates for renal transplantation. Prior experience demonstrated that HIV-positive renal transplant recipients had acceptable survival but graft survival was decreased and rejection rates were increased, possibly due to suboptimal management of immunosuppressive medications in the face of drug interactions with antiretroviral therapy, particularly protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Integrase strand transferase inhibitors are advantageous since they avoid drug-drug interactions with immunosuppressive drugs such as calcineurin inhibitors. We report clinical outcomes of 12 HIV-positive patients who underwent 13 kidney transplantations at our institution between 2000 and 2015. Cumulative survival was 75%, one-year and three-year survival were 100% and 63%. Integrase strand transferase inhibitor-based regimens were used in nine patients, of which eight survived. In patients on integrase strand transferase inhibitor, there was 100% graft survival and two had allograft rejection. In contrast, graft failure occurred in three patients on non-integrase strand transferase inhibitor-based regimens. Based on our study findings and on previously published data, we conclude that integrase strand transferase inhibitor-based therapy, preferably instituted prior to transplantation, is the preferred antiretroviral regimen in HIV-positive renal transplantation.
Int J STD AIDS 2017 04
PMID:Integrase strand transferase inhibitors: the preferred antiretroviral regimen in HIV-positive renal transplantation. 2719 21