Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myristoylation of the human immunodeficiency virus type 1 (HIV-1) proteins Gag and Nef by N-myristoyltransferase (NMT) is a key process in retroviral replication and virulence, yet remains incompletely characterized. Therefore, the roles of the two isozymes, NMT1 and NMT2, in myristoylating Gag and Nef were examined using biochemical and molecular approaches. Fluorescently labelled peptides corresponding to the N terminus of HIV-1 Gag or Nef were myristoylated by recombinant human NMT1 and NMT2. Kinetic analyses indicated that NMT1 and NMT2 had 30- and 130-fold lower K(m )values for Nef than Gag, respectively. Values for K(cat) indicated that, once Gag or Nef binds to the enzyme, myristoylation by NMT1 and NMT2 proceeds at comparable rates. Furthermore, the catalytic efficiencies for the processing of Gag by NMT1 and NMT2 were equivalent. In contrast, NMT2 had approximately 5-fold higher catalytic efficiency for the myristoylation of Nef than NMT1. Competition experiments confirmed that the Nef peptide acts as a competitive inhibitor for the myristoylation of Gag. Experiments using full-length recombinant Nef protein also indicated a lower K(m) for Nef myristoylation by NMT2 than NMT1. Small interfering RNAs were used to selectively deplete NMT1 and/or NMT2 from HEK293T cells expressing a recombinant Nef-sgGFP fusion protein. Depletion of NMT1 had minimal effect on the intracellular distribution of Nef-sgGFP, whereas depletion of NMT2 altered distribution to a diffuse, widespread pattern, mimicking that of a myristoylation-deficient mutant of Nef-sgGFP. Together, these findings indicate that Nef is preferentially myristoylated by NMT2, suggesting that selective inhibition of NMT2 may provide a novel means of blocking HIV virulence.
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PMID:N-Myristoyltransferase isozymes exhibit differential specificity for human immunodeficiency virus type 1 Gag and Nef. 1808 53

N-Myristoyltransferase (NMT) isozymes, i.e., NMT1 and NMT2, are essential host factors for the AIDS-causing human immunodeficiency virus type-1 (HIV-1), by which the viral proteins Pr55(gag) and Nef are N-myristoylated. N-Myristoylation is important for the membrane targeting of modified proteins. Since it is predicted that approximately 0.5% of all proteins in the human genome are N-myristoylated, selective inhibition of closely HIV-1-associated NMT isozymes is thought to be important for the improvement of specificity in the anti-HIV-1 strategy with the inhibition of NMT function. NMT isozymes contain two characteristic structures, the N-terminal region and the catalytic region. Here, it was shown that the N-terminal region of each NMT isozyme is required for isozyme-specific binding to the ribosome. The specific binding of each isozyme to the ribosome was associated with HIV-1 production, in which NMT1 and NMT2 in the ribosome were suggested to be mainly related to Pr55(gag) and Nef, respectively. These results indicate that the N-terminal region that mediates binding to the ribosome can become a target for NMT-isozyme-specific inhibition, which could block HIV-1 production.
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PMID:Suppression of human immunodeficiency virus type-1 production by coexpression of catalytic-region-deleted N-myristoyltransferase mutants. 2113 44