Evidence for the role of vitamin B-6 as a cofactor of lysyl oxidase

J C Murray; C I Levene

doi:10.1042/bj1670463

Evidence for the role of vitamin B-6 as a cofactor of lysyl oxidase

Biochemical Journal ◽

10.1042/bj1670463 ◽

1977 ◽

Vol 167 (2) ◽

pp. 463-467 ◽

Cited By ~ 32

Author(s):

J C Murray ◽

C I Levene

Keyword(s):

Enzyme Activity ◽

Isonicotinic Acid ◽

Lysyl Oxidase ◽

Acid Hydrazide ◽

Single Peak ◽

Partial Purification ◽

Vitamin B ◽

Epiphysial Cartilage

At 24 h after injection of 16-day chick embryos with [C-3H]pyridoxine hydrochloride, some of this label appears in the epiphysial cartilage. Over 35% of this radioactivity appears in the form of [G-3H]pyridoxal and a further 30% as other vitamin B-6 compounds. Partial purification of lysyl oxidase from the labelled epiphysial cartilage reveals a single peak of radioactivity coinciding with a single peak of enzyme activity. On dialysis against phosphate-buffered saline, 75% of this radioactivity is found to be non-diffusible. After incubation with isonicotinic acid hydrazide, a carbonyl reagent that appears to inhibit lysyl oxidase both in vivo and in vitro, a further 70% of the radioactivity is lost, with a roughly corresponding loss of enzyme activity. It is suggested that a form of vitamin B-6 is required as a cofactor of lysyl oxidase, and that this may have important implications in terms of connective-tissue metabolism.

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Lysyl oxidase activity and elastin/glycosaminoglycan interactions in growing chick and rat aortas.

The Journal of Cell Biology ◽

10.1083/jcb.105.3.1463 ◽

1987 ◽

Vol 105 (3) ◽

pp. 1463-1469 ◽

Cited By ~ 60

Author(s):

C Fornieri ◽

M Baccarani-Contri ◽

D Quaglino ◽

I Pasquali-Ronchetti

Keyword(s):

Hydrophobic Interactions ◽

Isonicotinic Acid ◽

Lysyl Oxidase ◽

Acid Hydrazide ◽

Elastic Fibers ◽

Amino Groups ◽

Lysine Residues ◽

Oxidase Inhibition

Hydrophobic tropoelastin molecules aggregate in vitro in physiological conditions and form fibers very similar to natural ones (Bressan, G. M., I. Pasquali Ronchetti, C. Fornieri, F. Mattioli, I. Castellani, and D. Volpin, 1986, J. Ultrastruct. Molec. Struct. Res., 94:209-216). Similar hydrophobic interactions might be operative in in vivo fibrogenesis. Data are presented suggesting that matrix glycosaminoglycans (GAGs) prevent spontaneous tropoelastin aggregation in vivo, at least up to the deamination of lysine residues on tropoelastin by matrix lysyl oxidase. Lysyl oxidase inhibitors beta-aminopropionitrile, aminoacetonitrile, semicarbazide, and isonicotinic acid hydrazide were given to newborn chicks, to chick embryos, and to newborn rats, and the ultrastructural alterations of the aortic elastic fibers were analyzed and compared with the extent of the enzyme inhibition. When inhibition was greater than 65% all chemicals induced alterations of elastic fibers in the form of lateral aggregates of elastin, which were always permeated by cytochemically and immunologically recognizable GAGs. The number and size of the abnormal elastin/GAGs aggregates were proportional to the extent of lysyl oxidase inhibition. The phenomenon was independent of the animal species. All data suggest that, upon inhibition of lysyl oxidase, matrix GAGs remain among elastin molecules during fibrogenesis by binding to positively charged amino groups on elastin. Newly synthesized and secreted tropoelastin has the highest number of free epsilon amino groups, and, therefore, the highest capability of binding to GAGs. These polyanions, by virtue of their great hydration and dispersing power, could prevent random spontaneous aggregation of hydrophobic tropoelastin in the extracellular space.

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The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo

Biochemical Journal ◽

10.1042/bj2210837 ◽

1984 ◽

Vol 221 (3) ◽

pp. 837-843 ◽

Cited By ~ 18

Author(s):

M J Carrington ◽

T A Bird ◽

C I Levene

Keyword(s):

Pyridoxal Phosphate ◽

Isonicotinic Acid ◽

Lysyl Oxidase ◽

Acid Hydrazide ◽

Chick Embryos ◽

Cross Link ◽

Irreversible Inhibitor ◽

Link Formation

Isonicotinic acid hydrazide (isoniazid) causes a large increase in the salt-solubility of collagen when injected into chick embryos; this change is accompanied by the inactivation of lysyl oxidase (EC 1.4.3.13), the enzyme responsible for initiating cross-link formation in collagen and elastin. In addition, isoniazid markedly decreases the liver content of pyridoxal phosphate. The depletion of pyridoxal phosphate takes approx. 6 h, whereas the inhibition of lysyl oxidase and the increase in collagen solubility occur more slowly. A reversal of these effects of isoniazid can be produced by the subsequent injection of a stoichiometric amount of pyridoxal, supporting the role of pyridoxal as a cofactor for lysyl oxidase. Treatment of chick embryos with beta-aminopropionitrile, an irreversible inhibitor of lysyl oxidase, causes an inhibition of the enzyme, which begins to recover within 24 h but which is not affected by the administration of pyridoxal; with isoniazid inhibition, however, lysyl oxidase activity does not show any sign of recovery by 48 h. It is proposed that isoniazid may cause the inhibition of lysyl oxidase by competing for its obligatory cofactor, pyridoxal phosphate. The potential clinical implications in the therapeutic control of fibrosis are briefly discussed.

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Hybrid Design of Isonicotinic Acid Hydrazide Derivatives: Machine Learning Studies, Synthesis and Biological Evaluation of their Antituberculosis Activity

Current Drug Discovery Technologies ◽

10.2174/1570163816666190411110331 ◽

2020 ◽

Vol 17 (3) ◽

pp. 365-375

Author(s):

Vasyl Kovalishyn ◽

Diana Hodyna ◽

Vitaliy O. Sinenko ◽

Volodymyr Blagodatny ◽

Ivan Semenyuta ◽

...

Keyword(s):

Machine Learning ◽

Isonicotinic Acid ◽

Acid Hydrazide ◽

Predictive Ability ◽

Antitubercular Activity ◽

Biological Evaluation ◽

Starting Point ◽

Binary Classifiers ◽

Synthesis And Biological Evaluation

Background: Tuberculosis (TB) is an infection disease caused by Mycobacterium tuberculosis (Mtb) bacteria. One of the main causes of mortality from TB is the problem of Mtb resistance to known drugs. Objective: The goal of this work is to identify potent small molecule anti-TB agents by machine learning, synthesis and biological evaluation. Methods: The On-line Chemical Database and Modeling Environment (OCHEM) was used to build predictive machine learning models. Seven compounds were synthesized and tested in vitro for their antitubercular activity against H37Rv and resistant Mtb strains. Results: A set of predictive models was built with OCHEM based on a set of previously synthesized isoniazid (INH) derivatives containing a thiazole core and tested against Mtb. The predictive ability of the models was tested by a 5-fold cross-validation, and resulted in balanced accuracies (BA) of 61–78% for the binary classifiers. Test set validation showed that the models could be instrumental in predicting anti- TB activity with a reasonable accuracy (with BA = 67–79 %) within the applicability domain. Seven designed compounds were synthesized and demonstrated activity against both the H37Rv and multidrugresistant (MDR) Mtb strains resistant to rifampicin and isoniazid. According to the acute toxicity evaluation in Daphnia magna neonates, six compounds were classified as moderately toxic (LD50 in the range of 10−100 mg/L) and one as practically harmless (LD50 in the range of 100−1000 mg/L). Conclusion: The newly identified compounds may represent a starting point for further development of therapies against Mtb. The developed models are available online at OCHEM http://ochem.eu/article/11 1066 and can be used to virtually screen for potential compounds with anti-TB activity.

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Metabolic importance of Na+/K+-ATPase activity during sea urchin development.

Journal of Experimental Biology ◽

10.1242/jeb.200.22.2881 ◽

1997 ◽

Vol 200 (22) ◽

pp. 2881-2892 ◽

Cited By ~ 3

Author(s):

P Leong ◽

D Manahan

Keyword(s):

Enzyme Activity ◽

Atpase Activity ◽

Sea Urchin ◽

Sodium Pump ◽

Sea Water ◽

Strongylocentrotus Purpuratus ◽

Lytechinus Pictus ◽

Stimulation Of

Early stages of animal development have high mass-specific rates of metabolism. The biochemical processes that establish metabolic rate and how these processes change during development are not understood. In this study, changes in Na+/K+-ATPase activity (the sodium pump) and rate of oxygen consumption were measured during embryonic and early larval development for two species of sea urchin, Strongylocentrotus purpuratus and Lytechinus pictus. Total (in vitro) Na+/K+-ATPase activity increased during development and could potentially account for up to 77 % of larval oxygen consumption in Strongylocentrotus purpuratus (pluteus stage) and 80 % in Lytechinus pictus (prism stage). The critical issue was addressed of what percentage of total enzyme activity is physiologically active in living embryos and larvae and thus what percentage of metabolism is established by the activity of the sodium pump during development. Early developmental stages of sea urchins are ideal for understanding the in vivo metabolic importance of Na+/K+-ATPase because of their small size and high permeability to radioactive tracers (86Rb+) added to sea water. A comparison of total and in vivo Na+/K+-ATPase activities revealed that approximately half of the total activity was utilized in vivo. The remainder represented a functionally active reserve that was subject to regulation, as verified by stimulation of in vivo Na+/K+-ATPase activity in the presence of the ionophore monensin. In the presence of monensin, in vivo Na+/K+-ATPase activities in embryos of S. purpuratus increased to 94 % of the maximum enzyme activity measured in vitro. Stimulation of in vivo Na+/K+-ATPase activity was also observed in the presence of dissolved alanine, presumably due to the requirement to remove the additional intracellular Na+ that was cotransported with alanine from sea water. The metabolic cost of maintaining the ionic balance was found to be high, with this process alone accounting for 40 % of the metabolic rate of sea urchin larvae (based on the measured fraction of total Na+/K+-ATPase that is physiologically active in larvae of S. purpuratus). Ontogenetic changes in pump activity and environmentally induced regulation of reserve Na+/K+-ATPase activity are important factors that determine a major proportion of the metabolic costs of sea urchin development.

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Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury

Thorax ◽

10.1136/thoraxjnl-2020-216469 ◽

2021 ◽

pp. thoraxjnl-2020-216469

Author(s):

Alison W Ha ◽

Tao Bai ◽

David L Ebenezer ◽

Tanvi Sethi ◽

Tara Sudhadevi ◽

...

Keyword(s):

Lung Injury ◽

Lysyl Oxidase ◽

Critical Role ◽

Sphingosine Kinase ◽

In Vivo Studies ◽

Sphingosine Kinase 1 ◽

Neonatal Lung ◽

Neonatal Lung Injury

IntroductionNeonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.MethodThe enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).ResultsBoth SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.ConclusionHO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.

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In Vitro Antileishmanial Activity of Nicotinamide

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.2.808-812.2005 ◽

2005 ◽

Vol 49 (2) ◽

pp. 808-812 ◽

Cited By ~ 35

Author(s):

D. Sereno ◽

A. Monte Alegre ◽

R. Silvestre ◽

B. Vergnes ◽

A. Ouaissi

Keyword(s):

Leishmania Major ◽

Growth Arrest ◽

Antileishmanial Activity ◽

Vitamin B ◽

Wild Type ◽

Intracellular Growth ◽

Cell Growth Arrest ◽

Transgenic Parasites

ABSTRACT Our study represents the first report demonstrating the antileishmanial activity of nicotinamide (NAm), a form of vitamin B3. A 5 mM concentration of NAm significantly inhibited the intracellular growth of Leishmania amastigotes and the NAD-dependent deacetylase activity carried by parasites overexpressing Leishmania major SIR2 (LmSIR2). However, the transgenic parasites were as susceptible as the wild-type parasites to NAm-induced cell growth arrest. Therefore, we conclude that NAm inhibits leishmanial growth and that overexpression of LmSIR2 does not overcome this inhibition. The mechanism of the inhibition is not defined but may include other in vivo targets. NAm may thus represent a new antileishmanial agent which could potentially be used in combination with other drugs during therapy.

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Role of pyridoxal phosphate in mammalian polyamine biosynthesis. Lack of requirement for mammalian S-adenosylmethionine decarboxylase activity

Biochemical Journal ◽

10.1042/bj1660081 ◽

1977 ◽

Vol 166 (1) ◽

pp. 81-88 ◽

Cited By ~ 19

Author(s):

A E Pegg

Keyword(s):

Ornithine Decarboxylase ◽

Pyridoxal Phosphate ◽

Vitamin B ◽

Decarboxylase Activity ◽

Deficient Diet ◽

Polyamine Biosynthesis ◽

Adenosylmethionine Decarboxylase ◽

Ornithine Decarboxylase Activity

1. Polyamine concentrations were decreased in rats fed on a diet deficient in vitamin B-6. 2. Ornithine decarboxylase activity was decreased by vitamin B-6 deficiency when assayed in tissue extracts without addition of pyridoxal phosphate, but was greater than in control extracts when pyridoxal phosphate was present in saturating amounts. 3. In contrast, the activity of S-adenosylmethionine decarboxylase was not enhanced by pyridoxal phosphate addition even when dialysed extracts were prepared from tissues of young rats suckled by mothers fed on the vitamin B-6-deficient diet. 4. S-Adenosylmethionine decarboxylase activities were increased by administration of methylglyoxal bis(guanylhydrazone) (1,1′-[(methylethanediylidine)dinitrilo]diguanidine) to similar extents in both control and vitamin B-6-deficient animals. 5. The spectrum of highly purified liver S-adenosylmethionine decarboxylase did not indicate the presence of pyridoxal phosphate. After inactivation of the enzyme by reaction with NaB3H4, radioactivity was incorporated into the enzyme, but was not present as a reduced derivative of pyridoxal phosphate. 6. It is concluded that the decreased concentrations of polyamines in rats fed on a diet containing vitamin B-6 may be due to decreased activity or ornithine decarboxylase or may be caused by an unknown mechanism responding to growth retardation produced by the vitamin deficiency. In either case, measurements of S-adenosylmethionine decarboxylase and ornithine decarboxylase activity under optimum conditions in vitro do not correlate with the polyamine concentrations in vivo.

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Cytotoxicity and Antitumor Activity of Platinum(II) Complexes of Aromatic and Cycloalkanecarboxylic Acid Hydrazides

Zeitschrift für Naturforschung C ◽

10.1515/znc-1997-1-209 ◽

1997 ◽

Vol 52 (1-2) ◽

pp. 49-54 ◽

Cited By ~ 7

Author(s):

Daniel N. Kushev ◽

Nadejda C. Spassovska ◽

Svetoslav I. Taxirov ◽

Konstantin C. Grancharov

Keyword(s):

Antitumor Activity ◽

Acid Hydrazide ◽

In Vitro Cytotoxicity ◽

Macromolecular Synthesis ◽

H Nmr ◽

Antineoplastic Effect ◽

In Vivo Antitumor Activity ◽

Friend Leukemia

AbstractNew platinum(II) complexes of cyclohexanecarboxylic acid hydrazide (chcah) were synthesized and characterized by elemental analysis, IR. and 1H NMR spectra. Their inhibitory effects on cell growth and macromolecular synthesis of Friend leukemia cells in culture as well as the in vivo antitumor activity towards L1210 leukemia in mice were compared with those of complexes containing differently substituted aromatic acid hydrazides. Some of the complexes exhibited antineoplastic activity. No correlation between the in vitro cytotoxicity and the in vivo antitumor activity was found. However, there was a relationship between the in vitro macromolecular synthesis inhibition profile and the in vivo antineoplastic effect, similar to that of cisplatin. On the other hand, only agents containing one ammine ligand were active in vivo. The substitution of the aromatic ring by a cycloalkane residue increased significantly the antitumor effect, with [Pt(NH3)(chcah)Cl2] being the most active compound in this study.

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Hereditary Nonspherocytic Hemolysis With Erythrocyte Phosphofructokinase Deficiency

Blood ◽

10.1182/blood.v39.3.415.415 ◽

1972 ◽

Vol 39 (3) ◽

pp. 415-425 ◽

Cited By ~ 25

Author(s):

Larry Waterbury ◽

Eugene P. Frenkel

Keyword(s):

Enzyme Activity ◽

Adenosine Triphosphate ◽

Lactate Production ◽

Kinetic Studies ◽

Glycogen Storage ◽

Muscle Disease ◽

Phosphofructokinase Activity ◽

Phosphofructokinase Deficiency

Abstract Hereditary nonspherocytic hemolysis associated with abnormal erythrocyte phosphofructokinase activity was demonstrated in a young man. Enzyme activity in the propositus, his mother, and maternal grandmother was approximately 60% of normal controls. There was markedly increased lability of enzyme activity on in vitro storage. Kinetic studies revealed increased sensitivity to adenosine triphosphate inhibition. Erythrocyte adenosine triphosphate levels were depressed. The absence of muscle disease and the presence of normal in vivo lactate production following ischemic exercise differentiated this kindred from those with Type VII glycogen storage disease.

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