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

Myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyzes the covalent attachment of myristic acid to the NH2-terminal Gly residues of a number of viral and cellular proteins. The remarkable specificity of this enzyme for myristoyl CoA observed in vivo appears to arise in large part from a cooperativity between NMT's acylCoA and peptide binding sites: the length of the acylCoA bound to NMT influences the interactions of peptide substrates with NMT. We have previously synthesized analogs of myristic acid with single oxygen or sulfur for methylene substitutions. These heteroatom substitutions produce significant reductions in acyl chain hydrophobicity without accompanying alterations in chain length or stereochemical restrictions. In vitro studies have shown that the CoA thioesters of these analogs are substrates for S. cerevisiae NMT and that the efficiency of their transfer to octapeptide substrates is peptide sequence-dependent. In vivo studies with cultured mammalian cells have confirmed that these fatty acid analogs are selectively incorporated into a subset of cellular N-myristoylproteins, that only a subset of analog-substituted proteins undergo redistribution from membrane to cytosolic fractions, and that these analogs can inhibit the replication of human immunodeficiency virus I and Moloney murine leukemia viruses--two retroviruses that depend upon N-myristoylation of their gag polyprotein precursors for assembly. We have now extended our analysis of NMT-acylCoA interactions by synthesizing additional analogs of myristic acid and testing them in a coupled in vitro assay system. Myristic acid analogs with two oxygen or two sulfur substitutions have hydrophobicities comparable to that of hexanoic acid and decanoic acid, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel fatty acyl substrates for myristoyl-CoA:protein N-myristoyl-transferase. 219 61

A series of platinum complexes of the form cis-M[PtA2(PC)] (I) has been prepared and tested for antitumor activity in mice. Compounds in this series contain either two monodentate amine ligands (A), such as NH3 or isopropylamine, or one bidentate diamine (A2), such as ethylenediamine, 1,2-diaminopropane, or 1,2-diaminocyclohexane. The PC ligand is a bidentate, O-bound, phosphono carboxylate chelate of the form -O2C(CR1R2)nPO3-, where n = 0 or 1 and R1 and R2 are chosen from H, methyl, ethyl, propyl, butyl, phenyl, or pentanoic acid substituents. The resulting complexes (I) were prepared as the free acids (M = H) or as sodium salts (M = Na). Members of this series have demonstrated good activity in a number of tumor screens. A total of 18 platinum-phosphono carboxylate (Pt-PC) complexes were tested against Sarcoma 180 ascites (S180a) in CFW mice, with 13 analogues showing activity above the 50% ILS level. Antitumor activity was also observed vs L1210 leukemia in CDF1 mice, where six of the 12 compounds tested gave ILS values in the 60-160% range, and vs M5076 reticulum cell sarcoma (sc tumor, iv drug), where four of the four compounds tested gave ILS and T-C values comparable to that of cisplatin. Each of the Pt-PC complexes was characterized by NMR (195Pt, 13C, and 31P), HPLC, and elemental analysis. These compounds, which are anionic at neutral pH, display excellent solubility and stability in aqueous media, such as phosphate-buffered saline and fetal calf serum. On the basis of a comparative study of BUN and serum creatinine levels in treated mice, representative complexes from this series are also less kidney toxic than cisplatin. The results of these studies demonstrate that the platinum-phosphono carboxylate complexes are a promising new class of antitumor agents.
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PMID:cis-diamineplatinum (II) complexes containing phosphono carboxylate ligands as antitumor agents. 229 7

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.
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PMID:Antitumor and DNA-binding properties of a group of oligomeric complexes of Pt(II) and Pt(IV). 237 44

The human NGF gene was isolated and inserted downstream from murine leukemia virus LTR in a plasmid having dihydrofolate reductase cDNA. The expression plasmid was introduced into CHO cells. Selection of the transformants for the resistance to methotrexate gave a CHO cell line which produced human NGF at a level of 4 mg/L in the culture medium. The recombinant human NGF was purified to near homogeneity from the culture supernatant. The NH2-terminal amino acid sequence, the COOH-terminal amino acid (Ala), and the amino acid composition of the human NGF were identical to those deduced from the nucleotide sequence of the human NGF gene. The recombinant human NGF was composed of 120 amino acid residues. Three disulfide linkages were determined to be Cys15-Cys80, Cys-58-Cys108, and Cys68-Cys110; the locations were identical to those in the mouse 2.5S NGF molecule. The specific biological activity of the recombinant human NGF was comparable with that of authentic mouse 2.5S NGF as determined by stimulation of neurite outgrowth from PC12 cells.
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PMID:Production, purification and characterization of biologically active recombinant human nerve growth factor. 239 85

Reverse transcriptase of murine retroviruses is a monomeric protein of approximately 80,000 daltons, which is encoded by the central portion of the viral pol gene. To prepare large quantities of the enzyme, we have constructed gene fusions between the trpE gene and portions of the pol gene of Moloney murine leukemia virus. The inserted pol gene sequences include the entire coding region for the mature enzyme and various amounts of additional coding sequences. Many of these constructs express high levels of reverse transcriptase activity even though the NH2 and COOH termini of the protein product only approximate the correct termini of the authentic protein.
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PMID:Expression of enzymatically active reverse transcriptase in Escherichia coli. 241 Sep 10

The NH2-terminal amino acid sequence of Moloney murine leukemia virus reverse transcriptase was determined to be Thr-Leu-Asn-Ile-Glu-Asp-Glu-Tyr-Arg-Leu-His-Glu-. The comparison of the amino acid analysis data obtained after carboxypeptidase Y digestion with the published nucleotide sequence (T. M. Shinnick, R. A. Lerner, and J. G. Sutcliffe, Nature (London) 293, 543-548, 1981) led to the conclusion that the COOH-terminus is Leu coded by CTC in nucleotide positions 4608-4610, and the tentative COOH-terminal sequence is Pro-Asp-Thr-Ser-Thr-Leu-Leu-OH. In light of these and previously reported results the complexity and map order of the pol gene are discussed.
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PMID:Amino- and carboxyl-terminal sequence of Moloney murine leukemia virus reverse transcriptase. 241 14

Inhibitory effects of 2',3'-dideoxythymidine 5'-triphosphate (ddTTP) and its three derivatives modified on the 3' position of ribose moiety [3'-azido-2',3'-dideoxythymidine 5'-triphosphate (3'-N3-ddTTP), 3'-amino-2',3'-dideoxythymidine 5'-triphosphate (3'-NH2-ddTTP) and 2'-deoxyxylo-furanosylthymine 5'-triphosphate (dXTP)] on the activity of the reverse transcriptase purified from Rauscher murine leukemia virus were examined and compared with each other. When (rA)n X (dT)12-18 was used as the template X primer in the presence of manganese ion, all these compounds except 3'-NH2-ddTTP inhibited the reverse transcriptase activity in competitive fashion with respect to the dTTP substrate. The inhibition potentials of these compounds are ordered as follows: 3'-N3-ddTTP (Ki = 1.8 microM) greater than ddTTP (Ki = 9.3 microM) greater than dXTP (Ki = 16.3 microM), and the Ki values of these inhibitors are smaller than the Km of dTTP (30 microM). The observed inhibitions were mainly due to competition between the dTTP substrate and inhibitor rather than chain-termination of the elongating DNAs caused by incorporation of these dideoxy compounds.
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PMID:Inhibition of reverse transcriptase activity by 2',3'-dideoxythymidine 5'-triphosphate and its derivatives modified on the 3' position. 243 May 67

The v-abl oncogene of the Abelson murine leukemia virus (A-MuLV) is known to efficiently transform NIH/3T3 fibroblasts in vitro and to cause an acute lymphosarcoma in susceptible murine hosts. The role of its relative, the bcr/abl gene product, in the etiology of human chronic myelogenous leukemia (CML) remains speculative. To assess the transforming properties of the bcr/abl gene product, complementary DNA clones encoding the CML-specific P210 bcr/abl protein were expressed in NIH/3T3 fibroblasts. In contrast to the v-abl oncogene product P160, the P210 bcr/abl gene product did not transform NIH/3T3 cells. Cell lines were isolated that expressed high levels of the P210 bcr/abl protein but were morphologically normal. During the course of these experiments, a transforming recombinant of bcr/abl was isolated which fuses gag determinants derived from helper virus to the NH2-terminus of the bcr/abl protein. This suggests that a property of viral gag sequences, probably myristylation-dependent membrane localization, must be provided to bcr/abl for it to transform fibroblasts.
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PMID:The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. 244 Jan 7

To test whether cellular protein kinases exist that phosphorylate D-amino acid residues, a method was developed for separating O-phospho-D-serine from O-phospho-L-serine and O-phospho-L-tyrosine from O-phospho-D-tyrosine. This was accomplished by converting these amino acids to the L-leucyl dipeptide derivatives followed by separation of the diastereomers by anion-exchange high-performance liquid chromatography. The enantiomeric content of these D- and L-residues were measured in hydrolysates of 32P-labeled proteins produced by the protein kinases of human erythrocytes and the tyrosyl protein kinase of the Abelson leukemia virus. We found no measurable D-phosphoserine in erythrocyte membrane proteins under conditions where a 1% content of this residue relative to L-phosphoserine would have been detected. These values can be used to place an upper hypothetical limit on the fraction of erythrocyte protein kinase activity that is specific for serine residues in the D-configuration. In separate experiments, we examined the specificity of the tyrosyl protein kinases. We found that all of the phosphotyrosine that we isolated from the erythrocyte band 3 NH2-terminal fragment and from the autophosphorylation of the Abelson virus tyrosyl kinase was in the L-configuration.
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PMID:The stereospecificity of protein kinases. 244 31

Novel antibodies were raised against a synthetic NH2-terminal myristoyl glycine moiety which is characteristic of N-myristoyl-proteins. Antisera raised against N-myristoyl-Gly-hemocyanin reacted with N-myristoyl-Gly-[125I]albumin. The immunoreaction was competed for by albumin conjugated with N-myristoyl-glycine, while underivatized albumin had no effect. Of the [3H]myristate-labeled proteins detected, pp60v-src, which is a transforming protein of Rous sarcoma virus, and p19gag and p17gag, which are core proteins in the human T-cell leukemia virus and the human immunodeficiency virus, were identified as N-myristoylated proteins by the radioimmunoprecipitation analyses with the antibody.
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PMID:Antibodies to an NH2-terminal myristoyl glycine moiety can detect NH2-terminal myristoylated proteins in the retrovirus-infected cells. 254 72


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