Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myristoyl-CoA:protein N-myristoyltransferase (NMT; EC 2.3.1.97) catalyzes the cotranslational linkage of myristate to the N-terminal glycine residues of several cellular, viral, and oncoproteins. We have recently synthesized a series of sulfur- and oxygen-substituted analogs of myristic acid that are similar in length to the 14:0 fatty acid yet have hydrophobicities equivalent to dodecanoate or decanoate. Previous in vitro enzyme assays and metabolic labeling studies indicate that some of these analogs are excellent substrates for NMT and are incorporated into subsets of cellular N-myristoyl proteins. Their sequence-specific incorporation probably arises from cooperative interactions between the acyl CoA and peptide binding sites of NMT. The human immunodeficiency virus 1 (HIV-1) and Moloney murine leukemia virus (MoMLV) depend on myristoylation of gag polyprotein precursors for assembly. We have tested four analogs--12-methoxydodecanoic acid, 10-propoxydecanoic acid, 5-octyloxypentanoic acid, and 11-ethylthioundecanoic acid--for their ability to block replication of these retroviruses. All reduce HIV-1 replication when incubated with CD4+ H9 cells for 10 days at 10-100 microM. 12-Methoxydodecanoic acid is most effective, producing a concentration-dependent decrease in (i) reverse transcriptase activity (to levels that were 5-10% of control at 20-40 microM), (ii) p24 levels, and (iii) syncytia formation. This degree of inhibition of HIV-1 replication is equivalent to that seen with 5 microM 3'-azido-3'-deoxythymidine and is accomplished without apparent toxicity, as measured by cell viability, protein, and nucleic acid synthesis. 5-Octyloxypentanoic acid inhibits MoMLV assembly in a dose-dependent fashion without accompanying cellular toxicity, while 12-methoxydodecanoic acid has no effect. These data suggest that the use of cellular NMT activity to deliver analogs of myristate with altered physical-chemical properties to proteins that undergo this cotranslational modification may represent an effective anti-viral therapeutic strategy as well as a way to investigate the role of covalently bound fatty acid in viral assembly.
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PMID:Replication of human immunodeficiency virus 1 and Moloney murine leukemia virus is inhibited by different heteroatom-containing analogs of myristic acid. 281 17

This epidemiologic investigation comprised separate studies of the risk of cancer, cause-specific mortality rates, risks for neurodegenerative diseases, and the risk of arrhythmia-related heart disease among employees exposed to extremely low-frequency (50-Hz) electromagnetic fields (EMF) in the Danish utility industry. All the employees in this industry were followed-up in several registers. The risk of disease was analyzed in relation to occupational exposure to EMF, latency, and duration of employment. A specific job-exposure matrix was developed and validated by comparison with direct measurements of EMF during a workday. Linkage with the Danish Cancer Register did not identify increased risks for the cancers suggested a priori to be associated with exposure to EMF, including leukemia, brain tumors, and breast cancer. Significantly increased risks for lung cancer and mesothelioma were identified for workers highly exposed to asbestos. Linkage with the National Mortality Register revealed a significantly increased overall mortality rate from amyotrophic lateral sclerosis (ALS), with an increasing trend with duration of employment and EMF exposure. In addition, a significantly increased mortality rate from electric accidents was observed. It was hypothesized that the observation of increased mortality from ALS was associated with exposure to EMF or electric shocks. No increased mortality rate from cardiovascular or cerebrovascular disease was observed. Linkage with the National Hospital Register also revealed an increased risk of ALS and, thereby confirmed the finding of an increased mortality rate for this disease in the previous study. Linkage of the cohort with the Multiple Sclerosis Register revealed an increased risk of multiple sclerosis, which was not, however, significant. Linkage with the Pacemaker Register showed no increased risk of severe arrhythmia-related heart disease. The second part of the study included the establishment of a large, nationwide cohort of mobile phone subscribers comprising some 420 000 persons. No increased risk was observed for the cancers considered a priori to be possibly associated with the radiofrequency fields emitted by mobile phones, which were brain tumors, including acoustic neuroma, salivary gland tumors, and leukemia. The data were analyzed by duration of phone use, latency, system used (NMT, GSM or both) and age at first subscription. A study of the incidence of ocular malignant melanoma in comparison with the annual increase among the mobile phone subscribers showed a highly stable incidence rate for this rare cancer in Denmark over close to 50 years of registration. On the basis of these studies and the scientific literature, it is concluded that occupational exposure to 50-Hz EMF is not associated with an increased risk of cancer, but that these fields, electric shocks, or some other unknown factor related to alternating current electricity may be associated with the risk of ALS. There is no clear evidence that 50-Hz EMF is associated with other neurodegenerative or cardiovascular diseases. At present, there is little, if any, evidence that the use of mobile phones is associated with cancer in adults, including brain tumors, acoustic neuroma, cancer of the salivary glands, leukemia, or malignant melanoma of the eye.
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PMID:Electromagnetic fields and health effects--epidemiologic studies of cancer, diseases of the central nervous system and arrhythmia-related heart disease. 1525 60