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PubMed1978

The effect of mechanical stretching of the myosin rod component (fragment LMMMM S-2) on the ATPase activity of myosin.

The binding of myosin to nylon fiber gives immobilized myosin with a considerable ATPase activity. Treatment of immobilized enzyme with papain results in the entire ATPase activity (known to be concentrated in myosin heads, (fragment HMM S-1)) being replaced from the fiber into the solution; this means that myosin is chemically bound to the fiber via its rod part (fragment LMM+HMM S-2). When nylon fiber is mechanically stretched, the ATPase activity of myosin attached to it sharply decreases; after relaxation of the fiber the enzymatic activity returns to the initial level. The detailed study of this phenomenon has shown that reversible inactivation of myosin upon fiber stretching is not the result of an altered microenvironment of the enzyme. The discovered regulatory effect is ascribed to deformation of myosin molecules induced by support stretching. Thus deformation of the myosin tail (not indispensable for ATPase since its cleaving-off does not alter the enzymatic activity) leads to decrease in the ATPase activity of the enzyme. The possible role of the above phenomenon in the mechanism of muscle contraction is discussed.

Adenosine Triphosphatases↗

PubMed1991

The mechanism for the inhibition of actin-activated ATPase of smooth muscle heavy meromyosin by calponin.

Calponin, an actin-binding protein, inhibited the acto-heavy meromyosin (HMM) MgATPase and lowered the binding of HMM to actin. The amount of calponin bound to actin or tropomyosin-actin was the same when the ATPase was inhibited 80-90%. While the KATPase was diminished only less than 2-fold in the presence of calponin, the Vmax was decreased 6-fold and 2-fold with actin and tropomyosin-actin, respectively. A comparison of the kinetic constants for the ATP hydrolysis obtained in the presence of actin-calponin and tropomyosin-actin-calponin revealed that the tropomyosin augmented the Vmax 5-fold from the inhibited level, but there was no effect on the KATPase.

Actins↗

PubMed1979

Detection of antibodies specific to sodium dodecyl sulfate-treated proteins.

Heavy meromyosin (HMM) denatured by sodium dodecyl sulfate (SDS) was injected into guinea pigs, either in the presence of 1 mg SDS/mg protein or after chromatography on Sephadex G-10 to remove detergent excess. Antigen-antibody interactions were analyzed by the microcomplement fixation technique. When HMM was injected in the presence of excess of SDS, the microcomplement fixation curves exhibited two maxima; one was specific to the random coil configuration of heavy meromyosin or myosin, and the other was common to several SDS-protein complexes. The latter peak disappeared when the excess SDS was removed from the immunogen by chromatography. Results showed the presence of antibodies directed either against SDS or against the non-specific SDS protein link.

Antibody Specificity↗

PubMed1990

In vitro killing of human malignant mesothelioma by photodynamic therapy.

Photodynamic therapy was investigated as a potential new modality for the treatment of human malignant mesothelioma (HMM) utilizing the H-MESO-1 HMM cell line and the photosensitizing agent, Photofrin-II (PF-II). Up-take of PF-II by H-MESO-1 was documented by incubating H-MESO-1 cells with PF-II and measuring the fluorescence at 625 nm following excitation at 400 nm. Cytotoxicity of photodynamic therapy was determined by incubating H-MESO-1 cells (2 X 10(5)) in microtiter plates for 24 hr with concentrations of PF-II varying from 0 to 10 micrograms/ml. The wells were exposed to gold vapor laser light (628 nm) in doses ranging from 0 to 24,000 J/m2. Twenty-four hours following treatment, [3H]thymidine (1 microCi) was added to each well. Cells were harvested 24 hr later and counted for tritium incorporation. Five replicates were performed for each combination of light and drug. Peak absorption of PF-II by H-MESO-1 was reached within 8 hr. Maximal doses of light alone caused minimal cell killing. PF-II without light was cytotoxic only at the highest concentrations. However, the combination of PF-II at concentrations at or above 2.5 micrograms/ml and light produced a significant increase in cytotoxicity. These data demonstrate that photodynamic therapy can effectively kill human malignant mesothelioma cells in vitro.

Cell Survival↗

PubMed1991

Single-dose quinidine treatment inhibits mexiletine oxidation in extensive metabolizers of debrisoquine.

Urinary elimination of unchanged mexiletine, p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and mexiletine N-glucuronide conjugate (MGC) was investigated before and after treatment with quinidine. All subjects were phenotyped as extensive metabolizers for debrisoquine oxidation. The total recovery of mexiletine and metabolites was significantly reduced after quinidine pretreatment. It is concluded that pretreatment with a very low dose of quinidine inhibits markedly the elimination of both major mexiletine metabolites (PHM and HMM) and likely decreases the overall elimination of mexiletine. That should lead to changes in mexiletine disposition and have clinical consequences during combination therapy with both drugs.

Debrisoquin↗

PubMed1984

Reproduction and teratology studies on hexamethylmelamine in the rat and rabbit.

The antineoplastic drug hexamethylmelamine (HMM) was evaluated for effects on reproduction and postnatal development in the rat and on embryonal and fetal development in the rat and rabbit. Daily po treatment of male rats for 62 days with doses of 0, 10, 20, or 40 mg/kg/day resulted in testicular atrophy, reduced fertility, and a possible dominant lethal mutagenic effect at the higher two dose levels. Alterations in morphology and function of the beta cells of the pancreatic islets were observed after treatment of males for more than 28 days with 20 or 40 mg/kg/day. The same dose levels administered to female rats for 14 days prior to breeding and through Day 13 or 20 of gestation had no adverse effects on fertility, but the highest dose was embryocidal and postnatal survival was decreased at both the 20- and 40-mg/kg/day dose levels. Similar effects on postnatal survival were observed when the drug was administered by gavage to rats during the last week of gestation and throughout the lactation period. Treatment of pregnant rats throughout organogenesis (Days 6 to 15) or for 4-day intervals during organogenesis (Days 6 to 9, 9 to 12, or 12 to 15) with po doses ranging from 20 to 80 mg/kg/day resulted in decreased body weight gain and food consumption, an increased resorption rate in dams receiving 80 mg/kg/day on Days 6 to 9, and decreased fetal weights at all dose levels and most treatment intervals. The incidence of minor skeletal defects was increased among litters of HMM-treated groups. Major fetal malformations were limited in number but were considered treatment related. Treatment of pregnant rabbits po on Days 6 to 18 of gestation with doses of 0, 20, 40, or 60 mg/kg/day did not result in an embryocidal or teratogenic effect. Treatment with 60 mg/kg/day did, however, result in decreased kit weights, indicating a mild embryo-fetotoxic effect.

Abnormalities, Drug-Induced↗

PubMed1995

Magnetic bead protamine-linked microtiter assay for detection of heparin using iodinated low-molecular-mass heparin-tyramine.

We have developed a competitive heparin binding assay employing protamine-coated magnetic beads for detection and measurement of heparin. The assay utilizes 125-iodine specifically bound to newly synthesized low-molecular-mass (LMM) heparin-tyramine. The tracer was stable over a period of 3 weeks, as demonstrated by gel filtration chromatography. The protamine-coated beads were found to be stable over at least two months. The heparin-tyramine bead assay had in buffer a lower detection limit of 0.04 microgram/ml and in plasma of 0.23 microgram heparin/ml. 50% binding was obtained at 0.7 microgram/ml and 20% binding at 4 micrograms/ml in plasma. The within assay coefficient of variation ranged from 9 to 28% for unfractionated, high molecular mass (HMM) heparin and from 12 to 15% for LMM-heparins in buffer system and in plasma. Various heparin fractions displaced the tracer from the protamine-coated magnetic beads to different extents. The validity of the assay was proven after intravenous administration of unfractionated and LMM-heparin in man. The elimination rate was similar using the heparin-tyramine bead assay compared with the anti-factor Xa coagulation assay. After intravenous dosing of LMM-heparin the maximal concentration was lower using the heparin-tyramine bead assay compared with the anti-factor Xa coagulation assay. The bead assay was found to be reproducible, valid, and rapid for measurement of the concentration of heparin preparations in purified systems and for HMM-heparin in plasma. Measurement of the concentration of LMM-heparin in plasma has a high coefficient of variation using the binding assay.

Binding, Competitive↗

PubMed1991

Flexibility in actin-myosin motility system revealed by in vitro motility assay.

Flexibility of myosin molecule was studied by in vitro motility assay in terms of the direction of actin movement. Electron microscopy showed that HMM scattered on a nitrocellulose surface can bind actin filaments and form arrowhead-like patterns. Actin filaments can move in both directions on tracks of HMM made on a nitrocellulose surface. Further, actin filaments can move bidirectionally along native thick filaments over their central bare zone. These observations indicate that there is considerable flexibility in a myosin molecule and that the direction of the movement is determined by the polarity of actin filaments.

Actins↗

PubMed1987

Movement of myosin fragments in vitro: domains involved in force production.

We have used the Nitella-based movement assay to localize the site of force production in myosin. Methods were developed to use nonfilamentous myosin or proteolytic fragments of myosin in place of the thick filaments used in the original assay. In the experiments described here, the tail of myosin or its subfragments is anchored via antibodies to the surface of small particles. Nonfilamentous myosin or its subfragments move along Nitella actin cables at speeds similar to those obtained with filamentous myosin. We generated short HMM, a myosin fragment containing the heads and only 400 A of the tail. Although short HMM lacks the "hinge" region proposed by Harrington to be the site of force generation, and is incapable of forming thick filaments, it moves along actin at speeds above 1 micron/sec. Therefore, neither a thick filament nor the carboxy-terminal 1100 A of the tail is required for movement along actin. The results indicate that force production occurs in or near the myosin heads.

Actins↗

PubMed1989

Lysosomal proteinase-sensitive regions in fast and slow skeletal muscle myosins.

We investigated the limited proteolysis of fast and slow myosins purified from rabbit psoas major and semimembranosus proprius muscles, respectively, by the main lysosomal proteinases: cathepsins B, H, L, and D. In EDTA containing buffer, cathepsin D cleaved both myosins only at the rod-S1 junction leading to the formation of two S1 fragments of slightly higher Mr than the three forms obtained with chymotrypsin. On addition of MgCl2 instead of EDTA, myosin hydrolysis was markedly reduced. In contrast, irrespective of the presence of either MgCl2 or EDTA, cathepsin B hydrolysed both myosins into HMM and LMM. Cathepsin L digested myosins more extensively than cathepsins B and D and the main fragments generated were, in decreasing order of importance, rod, S1, S2, HMM, and LMM. In the incubation conditions tested, cathepsin H displayed nondetectable action on myosins. As fast and slow myosin digest patterns were compared, the main differences observed concerned the size of the proteolytic products and the rate of hydrolysis, which was about 4-fold higher for the fast than for the slow isoform. This appeared consistent whatever enzyme was considered.

Animals↗

PubMed1984

The curative action of hexamethylmelamine on intramuscularly or intracerebrally implanted Yoshida sarcoma.

Curative effects of hexamethylmelamine (HMM, NSC 13875) against intramuscularly or intracerebrally implanted Yoshida sarcoma depend on the schedules. A twice daily oral administration over a 2-week period showed a significant chemotherapeutic advantage over a single daily administration. The observed curative effect depends on the tumour site and on its mass. The Yoshida sarcoma seems to be one of the most suitable test models for HMM or related derivatives.

Altretamine↗

PubMed1992

Cystatins and stefins in ascites fluid from ovarian carcinoma.

Cysteine proteinase inhibitors (CpI) of all three families were found in ascites fluid from patients with ovarian carcinoma. CPIs were isolated by affinity chromatography on carboxymethylated papain Sepharose, followed by gel filtration, anti-stefin-Sepharose and ion exchange chromatography. The highest apparent inhibition against cathepsin B (Cat B) was found in the low molecular mass (LMM) CPI fraction. Immunochemical analysis of this fraction revealed the presence of cystatin C and both stefins A and B while the high molecular mass (HMM) CPI fraction contained kininogens. We demonstrated that CPIs were not completely associated with cysteine proteinases (CPs): about 20% of HMM CPIs and 50% of LMM CPIs were free in native ascites fluid. Affinity chromatography on anti-Cat B-Sepharose revealed that the major LMM CPI, associated with Cat B in native ascites fluid, was the full length form of cystatin C, pI 9.3, and not its truncated form, pI 7.85. The latter was isolated and found to inhibit Cat B in vitro with apparent Ki 0.18 +/- 0.2 nM. Stefin A was isolated from alkaline activated ascites fluid in its two isoforms, pI 4.6 and 4.9. In native ascites, the pI 4.9 isoform was mostly associated with Cat B. Ki for Cat B was 3.55 +/- 1.7 nM, not significantly different from the Ki values measured for stefin A, isolated from other human tissues and biological fluids.

Adult↗

PubMed1993

High-performance liquid chromatographic method for resolving the enantiomers of mexiletine and two major metabolites isolated from microbial fermentation media.

(+/-)-Mexiletine is a class Ib antiarrhythmic drug useful in the treatment of premature ventricular contractions. It is predominantly metabolized by the liver with less than 15% being excreted in urine as unchanged drug. p-Hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM) are the two major mammalian metabolites. The purpose of our study was to develop a stereospecific high-performance liquid chromatographic (HPLC) method to determine whether the fungus, Cunninghamella echinulata (UAMH 4145), was able to biosynthesize these same two metabolites from the substrate (+/-)-mexiletine. Furthermore, it was desirable to ascertain whether metabolism of mexiletine was stereoselective. The method requires pre-column derivatization of the drug and metabolites with S-(+)-1-(1-naphthyl)ethyl isocyanate (NEIC) followed by normal-phase HPLC. Mexiletine, PHM, HMM and (+/-)-1-(4-hydroxyphenoxy)-3-isopropylaminopropan-2-ol (internal standard) were extracted from microbial broth using two volumes of diethyl ether after basifying with sodium carbonate. The combined ether extracts were evaporated to dryness, using a gentle stream of nitrogen, and reconstituted in 0.3 ml of chloroform to which was added 0.075 ml of NEIC (0.1%, v/v, in chloroform). This solution was immediately evaporated to dryness under a nitrogen stream. The residue was reconstituted with 0.220 ml of chloroform and 0.030 ml of n-butylamine (0.33%, v/v, in chloroform) and injected into the HPLC system.

Chromatography, High Pressure Liquid↗

PubMed1992

Comparative investigation of disposition of 3,4-(methylenedioxy)methamphetamine (MDMA) in the rat and the mouse by a capillary gas chromatography-mass spectrometry assay based on perfluorotributylamine-enhanced ammonia positive ion chemical ionization.

A gas chromatography-mass spectrometry assay based on perfluorotributylamine-enhanced ammonia positive ion chemical ionization has been developed for MDMA and three of its primary metabolites in biological specimens; the assay is linear from 2 to 1000 ng ml-1. Quantitatively, more of an administered dose of 10 mg kg-1 MDMA was excreted by the mouse (72%) than by the rat (35%); most in both species was excreted in urine and within 24 h. The difference in per cent excretion is entirely due to proportionally greater excretion of the parent drug by the mouse. 4-Hydroxy-3-methoxymethamphetamine (HMM) is the major urinary metabolite in both species. HMM and another primary metabolite, 4-hydroxy-3-methoxyamphetamine (HMA), were excreted mainly as glucuronide and sulphate conjugates (> 85%).

3,4-Methylenedioxyamphetamine↗

PubMed1995

A phase II study of carboplatin and hexamethylmelamine as induction chemotherapy in advanced epithelial ovarian carcinoma.

27 patients with ovarian cancer FIGO stages IIc-IV were treated with carboplatin 7 x (glomerular filtration rate + 25) mg given intravenously on day 1 and hexamethylmelamine (HMM) 150 mg/m2 orally on days 2-15, every 28 days. 3 patients were not evaluable for response. Clinical response was seen in 17 patients (71%), with six (25%) complete and 11 (46%) partial responses. The median progression-free survival was 15.6 months and the median cancer-related survival was 21.3 months. 4 patients (15%) experienced grade 3 mental depression; none had peripheral neuropathy above grade 1. The haematological toxicity was moderate, none had grade 4 leucopenia, but 4 (15%) had grade 4 thrombocytopenia. Carboplatin plus HMM had few side-effects and a high response rate with a survival comparable to other platinum-based combinations.

Adult↗

PubMed2005

An investigation by electron microscopy of chylomicron remnant uptake by human monocyte-derived macrophages.

Human monocyte-derived macrophages (HMM) internalise proatherogenic chylomicron remnants via several high affinity receptor pathways. However, the endocytic ultrastructures responsible for the uptake of chylomicron remnants by macrophages have not previously been described. In this study, we have utilised transmission electron microscopy together with colloidal gold-labelling of chylomicron remnants to investigate the pathways involved in macrophage uptake of chylomicron remnants. We found that macrophages internalise chylomicron remnants via surface-connected compartments of up to 600 nm as well as non-clathrin coated pits. Chylomicron remnants were found to be distributed internally in a number of endocytic vesicles including early cysternal endosomes, spherical late endosomes and tubular vesicular compartments. Uptake of chylomicron remnants by HMM via phagocytosis or macropinocytosis was excluded based on the observations that lipoproteins were not found in phagolysosomes nor modified by inhibitors of these two processes, respectively. The latter observation contrasts with previous reports of chylomicron remnant internalisation by macrophages of other species.

Biological Transport↗

PubMed2006

Deciphering function and mechanism of calcium-binding proteins from their evolutionary imprints.

Calcium-binding proteins regulate ion metabolism and vital signalling pathways in all living organisms. Our aim is to rationalize the molecular basis of their function by studying their evolution using computational biology techniques. Phylogenetic analysis is of primary importance for classifying cognate orthologs; profile hidden Markov models (HMM) of individual subfamilies discern functionally relevant sites by conservation probability analysis; and 3-dimensional structures display the integral protein in context. The major classifications of calcium-binding proteins, viz. EF-hand, C2 and ANX, exhibit structural diversity in their HMM fingerprints at the subfamily level, with functional consequences for protein conformation, exposure of receptor interaction sites and/or binding to membrane phospholipids. Calmodulin, S100 and annexin families were characterized in Petromyzon marinus (sea lamprey) to document genome duplication and gene creation events during the key evolutionary transition to primitive vertebrates. Novel annexins from diverse organisms revealed calcium-binding domains with accessory structural features that define their unique molecular fingerprints, protein interactivity and functional specificity. These include the first single-domain, bacterial annexin in Cytophaga hutchinsonii, the 21 tetrad annexins from the unicellular protist Giardia intestinalis, an ancestor to land plant annexins from the green alga Ostreococcus lucimarinus, invertebrate octad annexins and a critical polymorphism in human ANXA7. Receptor docking models supported the hypothesis of a potential interaction between annexin and C2 domains as a propitious mechanism for ensuring membrane translocation during signal transduction.

Amino Acid Sequence↗

PubMed2004

Scoring hidden Markov models to discriminate beta-barrel membrane proteins.

A new method is presented for identification of beta-barrel membrane proteins. It is based on a hidden Markov model (HMM) with an architecture obeying these proteins' construction principles. Once the HMM is trained, log-odds score relative to a null model is used to discriminate beta-barrel membrane proteins from other proteins. The method achieves only 10% false positive and false negative rates in a six-fold cross-validation procedure. The results compare favorably with existing methods. This method is proposed to be a valuable tool to quickly scan proteomes of entirely sequenced organisms for beta-barrel membrane proteins.

Algorithms↗