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Hunting poisons of the North Pacific Region.

The hunting poisons of the North Pacific region are discussed. The most important one used by the Ainu was based on Aconitum species (surku or suruku): on Hokkaido, to some extent A. japonicum Thumb. but probably mainly A. yezoense Nakai and A. sachalinense Fr. Schm.; on southern Sakhalin, perhaps A. fischeri Reichb., A. maximum Pall. ex DC., and/or A. sachalinense Fr. Schm.; and on the Kuril Islands, A. maximum Pall. ex DC. Poison from the Japanese stingray Dasyatis akajei (Müller et Henle) (aikor chiep) was also much used, alone or mixed with aconite, and was believed by some Ainu to be better than aconite. Adjuvants to these poisons were numerous and varied in each locality. Daphne kamtschatica Maxim. var. yezoensis (Maxim.) Ohwi (ketuhas) was used in hunting walrus. The use of Cynanchum caudatum (Miq.) Maxim. (penup) enabled birds to be caught. Juglans ailanthifolia Carr (nesko) was a fish poison. A critical evaluation of the accounts by Krasheninnikov, Steller, Harms, and others, indicates that the inhibitants of the Kamchatka Peninsula, the Kamchadal (Itelmen), hunted with a poison derived from Aconitum maximum Pall. ex DC. This same species was almost certainly used in the Aleutian Islands and the Kodiak Island region, principally for hunting whales. There is some evidence that the inhabitants of the far north-eastern part of Siberia and of the Alaskan coasts opposite may also have used poison in hunting. The chemistry and toxicology of the poisons are briefly considered.

Aconitum↗
PubMed1993

Automated docking in crystallography: analysis of the substrates of aconitase.

Automated docking of substrates to proteins of known structure aids the process of crystallographic analysis in two ways. First, automated docking can be used to generate a small number of starting models for substrates using only protein coordinates from an early stage of refinement. Second, automated docking provides a method for exploring aspects of catalysis that are inaccessible to crystallography by postulating binding modes of catalytic intermediates. This paper describes the use of automated docking to explore the binding of substrates to aconitase. The technique starts with a substrate molecule in an arbitrary configuration and position and finds favorable docked configurations in a (static) protein active site based on a molecular mechanics type force field. Using protein coordinates from an early stage of refinement of an aconitase-isocitrate complex, we successfully predicted the binding configuration of isocitrate. Four configurations were found, the energetically most favorable of which fit the observed electron density well and was used as a starting model for further refinement. Two configurations were found in citrate docking experiments, the second of which approximates the mode of substrate binding in an aconitase-nitrocitrate complex. We were also able to propose two binding modes of the catalytic intermediate cis-aconitate. These correspond closely to the isocitrate and the citrate binding modes. The relation of these new results to the proposed reaction mechanism is discussed.

Aconitate Hydratase↗
PubMed1977

[Enzymatic examination of citrate-isocitrate accumulation in yeasts].

The activities of the enzymes citrate synthase, aconitate hydratase, isocitrate dehydrogenase and isocitrate lyase in cell homogenates of n-paraffin grown citrate plus isocitrate accumulating yeasts (C. lipolytica high rate accumulating strain and C. guilliermondii low rate accumulating strain) were determined. It is shown that the activities of the enzymes decline after transition from tropho- to idiophase and remain constant with exception of isocitrate lyase which diminishes slowly. The decline in activity of the isocitrate lyase was greatest in the cells of C. guilliermondii. It is discussed that the differences of the enzymatic activities in the tropho- and idiophase, resp. may be artefacts due to changes in the structure of cellular envelope, but that the decline of lyase activity in the idiophase could be one factor determining the rate of citric- and isocitric acid overproduction. The diminishing of isocitrate lyase in the course of idiophase is interpreted as example of a disappearing enzyme no further needed for normal function of the cells.

Aconitate Hydratase↗
PubMed1983

[Enzymatic study of citrate-isocitrate accumulation in yeast with glucose as the carbon source].

The connection between the kinetics of citrate-isocitrate overproduction by Saccharomycopsis lipolytica in glucose media and the specific activities of the enzymes being related to overproduction has been investigated. The specific activities of citrate synthase, aconitate hydratase, NAD+-linked and NADP+-linked isocitrate dehydrogenase decline significantly after exhaustion of the nitrogen source, whereas the activity of the pyruvate carboxylase remains relatively constant and corresponds to changes of the production rate. The results are compared with those obtained by fermentations in n-alkane media and discussed in relation to mechanisms of overproduction.

Aconitate Hydratase↗
PubMed1994

Kinetics of enzymes with iso-mechanisms: dead-end inhibition of fumarase and carbonic anhydrase II.

Isomerization of free enzyme can be detected in kinetic patterns of dead-end inhibition because competitive substrate analogs yield noncompetitive inhibition versus product in reverse reaction kinetics. The ratio of slope and intercept inhibition constants allows a quantitative estimation of the relative kinetic significance of the isomerization to a catalytic turnover. Applying this kinetic analysis theoretically to inhibition data for bovine carbonic anhydrase II by anions [Y. Pocker and T. L. Deits (1982) J. Am. Chem. Soc. 104, 2424] provides an estimate of 43 +/- 13% for how rate-limiting the isomerization segment is at pH 6.6. Applying the analysis experimentally to porcine heart fumarase provides a competitive pattern of inhibition by trans-aconitate versus fumarate with Ki(s) = 2.0 +/- 0.5 mM, together with a non-competitive pattern versus malate, with Ki(s) = 0.8 +/- 0.1 mM and Kii = 2.3 +/- 0.4 mM. Assuming that the isomerization segment of fumarase is the reprotonation of an active site carboxyl and imidazole with pK1 = 5.53 and pK2 = 7.78 [Blanchard and Cleland (1980) Biochemistry 19, 4506], an apparent rate constant for the isomerization segment of fumarate hydration is estimated as 95 +/- 22 s-1, compared to 42 +/- 13 s-1 for the chemical segment and 29 +/- 0.7 s-1 for a complete turnover. In contrast, the values are 17000 +/- 5200, 82 +/- 25, and 82 +/- 3 s-1, respectively, for malate dehydration. Hence, the isomerization segment is 30 +/- 7% rate-limiting during fumarate hydration but less than 1% during malate dehydration.

Aconitic Acid↗
PubMed1995

Fatty acid synthesis from glutamate in the adipose tissue of normal subjects and obese patients: an enzyme study.

In the adipose tissue, besides fatty acid synthesis (FA-S) from glucose, which includes several mitochondrial steps, FA-S from glutamate has been demonstrated. FA-S from glutamate takes place in the cytosol through the backward pathway of Krebs cycle (BPKC) and is due to the sequential action of (1) alanine aminotransferase (ALT, EC 2.6.1.2), which is presence of pyruvate converts glutamate to oxoglutarate; (2) isocitrate dehydrogenase (NADP) (ICDH, EC 1.1.1.42), which converts oxoglutarate to isocitrate; (3) aconitate hydratase (ACO, EC 4.2.1.3), which transforms isocitrate to citrate: and (4) ATP citrate-lyase (ATP-CL, EC 4.1.3.8), which splits citrate to yield the acetyl-CoA needed for FA-S. We studied the enzymes involved in BPKC in homogenates of human adipose tissue. In normal subjects, the cytosolic activity (mumol/min/g protein) was: ALT = 10.3 +/- 1.1, ICDH = 29.5 +/- 2.8, ACO = 2.05 +/- 0.23, and ATP-CL = 1.2 +/- 0.2. Mitochondria contained less or no activity, values being 20, 9, 11, and 0% of total for ATL, ICDH, ACO, and ATP-CL, respectively. BPKC enzymes are more active than the enzymes limiting FA-S from glucose, i.e., phosphofructokinase (EC 2.7.1.11), pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase (EC 1.2.4.1). In the obese patients, cytosolic ALT and ATP-CL were increased (12.9 +/- 0.7, P < 0.05, and 2.28 +/- 0.27, P < 0.01, respectively) compared to normal, while ICDH was not changed (ACO could not be studied). Similar changes were obtained by expressing enzyme activity per fat cell number.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Citrate (pro-S)-Lyase↗
PubMed1996

Preliminary determination of a molecular basis of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS/ME) is a debilitating fatigue illness that has an unknown etiology. We studied 20 chronic fatigue syndrome (CFS) patients, who complied with the Oxford and American CDC definitions, and 45 non-CFS subjects. Participants completed questionnaires, were clinically examined, and had first morning urine specimens collected, which were screened by gas chromatography-mass spectrometry for changes in metabolite excretion. Multivariate analysis of the urinary metabolite profiles differed significantly in the CFS patients compared to the non-CFS patients (P < 0.004). The CFS patients had increases in aminohydroxy-N-methylpyrrolidine (P < 0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (P < 0.02), beta-alanine (P < 0.02), aconitic acid (P < 0.05), and succinic acid (P < 0.05) and reductions in an unidentified urinary metabolite, CFSUM2 (P < 0.0007), alanine (P < 0.005), and glutamic acid (P < 0.02). CFSUM1, beta-alanine, and CFSUM2 were found by discriminant function analysis to be the first, second, and third most important metabolites, respectively for discriminating between CFS and non-CFS subjects. The abundances of CFSUM1 and beta-alanine were positively correlated with symptom incidence (P < 0.01 and P < 0.001, respectively), symptom severity, core CFS symptoms, and SCL-90-R somatization (P < 0.00001), suggesting a molecular basis for CFS.

Aconitic Acid↗
PubMed1997

Leishmania spp.: nitric oxide-mediated metabolic inhibition of promastigote and axenically grown amastigote forms.

The antimicrobial effect of activated macrophages on parasites involves nitric oxide (NO). NO induces intracellular parasite killing in murine leishmaniasis. Nevertheless, the mechanisms of action of NO as a final effector molecule on intracellular forms of Leishmania are unknown. The recent development of axenically grown amastigote forms of different Leishmania species allowed direct investigation of NO activity on active and dividing populations of the mammalian stage of various Leishmania species, which normally are only found intracellularly. Authentic NO gas, which reproduced the antimicrobial effect elaborated by activated macrophages, was flushed on promastigote and axenically cultured amastigote forms of L. mexicana, L. amazonensis, and L. chagasi suspended in degassed phosphate-buffered saline (PBS). After NO treatment, the viability of parasites gradually decreased as a function of time postflushing when compared to controls. Interestingly NO killing was more effective on promastigote forms than on amastigote forms. After 12-hr postflushing incubation in PBS, cultures of NO-treated parasites, contrary to controls (N2-treated), failed to proliferate whatever the species and the developmental stage considered. Addition of both FeSO4 and L-cysteine to PBS immediately after NO treatment reversed the capacity of authentic NO gas to inhibit the multiplication of both parasite stages of Leishmania. Supplementation of PBS with alpha-ketoglutarate and cis-aconitate (citric acid cycle substrates) also reversed the leishmanicidal activity of NO, whereas addition of citrate was less effective. The course of the developmental life cycle in vitro was also inhibited by NO gas treatment. Enzymatic analysis showed that aconitase activity was dramatically reduced by NO gas, whereas glucose phosphate isomerase, aspartate transferase, and phosphoglucomutase activities were unchanged. In accordance, promastigote and amastigote forms of Leishmania were shown to be killed by antimycin A, an inhibitor of mitrochondrial respiration. All these data demonstrated that NO action led to lethal metabolic inhibition in both developmental parasite stages by, at least in part, triggering iron loss from enzyme(s) with iron-sulfur prosthetic groups, in particular aconitase.

Aconitate Hydratase↗
PubMed1987

Genetic mapping, distribution, and properties of an aconitase isozyme in Anopheles albimanus (Diptera:Culicidae).

Electrophoretic analysis of the developmental stages and tissues of Anopheles albimanus showed that qualitatively similar allozymes of aconitase (Acon-2) occur at all stages, and the enzyme is widespread in every larval and adult tissues. Relative heat stabilities of the allozymes were investigated by electrophoresis of heated aqueous extracts and by heating the enzyme in situ in acrylamide gels after electrophoretic separation in Tris-citrate and Tris-maleate buffer systems. The pupal aconitase in the crude extract is more stable to heat than the larval and adult enzyme. The presence of citrate ions in the gel increased the stability of aconitase to heat. Studies of substrate specificities indicated that cis-aconitic acid is the best substrate but citric acid can also serve as a substrate. Zymograms developed with isocitric acid as a substrate showed no aconitase electromorphs and produced only isocitrate dehydrogenase bands. Aconitase has a pH optimum of 8.0 and this enzyme is completely inhibited if treated in situ with ethylenediaminetetra-acetic acid (EDTA), p-chloromercuribenzoate (PCMB), and urea at concentrations higher than 5 mM, 5 X 10(-5) M, and 2 M, respectively. Acon-2(100) and Acon-2(105) do not respond differently to the above treatments. Genetic crosses involving a holandric translocation, pericentric inversions, visible mutants, and allozyme markers were analyzed to map the aconitase (Acon-2) locus on the left arm of chromosome 3. The gene sequence (and map distances) on 3L is centromere-esterase-8 (Est-8)-2-esterase-4 (Est-4)-25-esterase-2 (Est-2)-9-Acon-2-5-phosphoglucomutase (Pgm)-7-esterase-6 (Est-6).

Aconitate Hydratase↗
PubMed1976

Growth and synthesis of rubratoxin by Penicillium rubrum in a chemically defined medium fortified with organic acids and intermediates of the tricarboxylic acid cycle.

A sterile glucose-mineral salts broth was fortified with equimolar concentrations (10--3 M) of various organic acids and intermediates in the tricarboxylic acid cycle. Appropriate media were neutralized with 2 N NaOH, inoculated with spore suspensions or mycelial pellets of Penicillium rubrum and incubated quiescently for 14 days or with shaking for 5 days. Rubratoxins were recovered from culture filtrates by ether extraction and resolved by thin-layer chromatography. Toxin formation in quiescent cultures was enhanced by malonate but was not markedly affected by ethyl malonate, shikimate, and acetate or by isocitrate or oxaloacetate added in the presence of malonate. Citrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, and malonate when present in the medium alone or in conjunction with malonate caused a 15 to 50% reduction in rubratoxin formation. Acetyl-CoA (10--5 M/flask) caused an 80% increase in toxin yield. Rubratoxin formation in shake cultures was not affected by succinate and malonate. All other combinations of intermediates and malonate caused a 10 to 50% reduction in toxin formation. At 10--3 M, citrate enhanced rubratoxin B formation and stimulated rubratoxin A production by as much as 100%. Above 10--3 M, citrate inhibited toxin production. Incorporation of [2-14C]acetate into rubratoxin was enhanced by malonate, fumarate, and malonate. A combination of pyruvate and malonate produced a 40% increase in [2-14C]acetate incorporation into rubratoxin. The highest reduction of labeled acetate incorporation (36%) was caused by succinate or alpha-ketoglutarate combined with malonate.

Acetates↗
PubMed2003

Basolateral localization of flounder Na+-dicarboxylate cotransporter (fNaDC-3) in the kidney of Pleuronectes americanus.

The purpose of this study was to provide functional and immunocytochemical evidence for the location of the winter flounder ( Pleuronectes americanus) sodium-dicarboxylate cotransporter-3 (fNaDC-3) in the basolateral membrane of proximal tubule cells. fNaDC-3 was expressed in Xenopus laevis oocytes. Lowering the external pH from 7.5 to 6.5 or 5.5 modestly decreased the uptake of [(14)C]succinate into fNaDC-3 expressing oocytes, but markedly increased the uptake of [(14)C]citrate. As measured by the two-electrode voltage-clamp technique, the citrate concentration eliciting half-maximal current, K(0.5), decreased from 490 microM at pH 7.5 to 32 microM at pH 6.0. The maximal inwards current, Delta I(max), increased from -27 to -72 nA, when bath pH was changed from 7.5 to 6.0. These data suggest that fNaDC-3 translocates preferably divalent citrate. cis-Aconitate, a tricarboxylate that interacts exclusively with basolateral sodium-dicarboxylate cotransport in the rat kidney, was translocated by fNaDC-3 with a K(0.5) of 300 microM. Antibodies raised against an NaDC-3-specific peptide reacted with the basal cell side of flounder renal proximal tubule segment II (PII). No other structures were stained, indicating that fNaDC-3 is located exclusively in the basolateral membrane of PII cells. We assume that fNaDC-3 provides PII cells with Krebs cycle intermediates as fuels and with alpha-ketoglutarate to drive organic anion secretion.

Aconitic Acid↗
PubMed1991

Phloretin and citrate promote the differentiation rate from epimastigote to metacyclic forms of Trypanosoma cruzi.

We have investigated the effects of the metabolic inhibitors, phloretin, 2-deoxy-D-glucose, maleate and trans-aconitate, as well as two intermediates of the tricarboxylic-acid cycle, acetate and citrate, on the growth and metacyclogenesis of Trypanosoma cruzi. 0.1 mM phloretin increased the percentage of metacyclic forms about 2.7-fold without affecting growth rate, whereas the other inhibitors had no apparent effect on either growth or differentiation rates. The addition of 5 mM citrate stimulated differentiation by about 2.6-fold. When either 10 mM citrate or 10 mM acetate were added, on the other hand, both the growth and differentiation rates were severely inhibited.

Acetates↗
PubMed1993

Altered intracellular polyamines in bloodstream form Trypanosoma brucei brucei: transformation to procyclic trypomastigotes.

A monomorphic strain of Trypanosoma brucei brucei (EATRO 110) was cultured as long slender bloodstream forms in vitro for 24 h with 100 microM Eflornithine HCl. This resulted in depletion of intracellular putrescine, a greater than 50% decrease in spermidine, and a cessation of cell division. These Eflornithine treated trypanosomes were stimulated to synchronously transform to procyclic trypomastigotes by transfer into SDM-79 medium containing the citric acid cycle intermediates citrate and cis-aconitate (CCA). Within 48 h morphological transformation was complete and occurred without any increase in cell numbers. The coadministration of 100 microM putrescine with Eflornithine prevented the depletion of putrescine and abrogated the cytostatic effect of Eflornithine alone, but did not prevent the transformation to procyclic trypomastigotes. Eflornithine-induced short stumpy form trypanosomes resulting from 4 days of culture with 100 microM Eflornithine did not transform to procyclic trypomastigotes in SDM-79 medium unless it contained CCA. We conclude that the high concentration of CCA can trigger transformation in all morphological types of bloodstream form trypanosomes, regardless of their threshold of sensitivity for the stimulus. Furthermore, the CCA-stimulated transformation is not dependent on putrescine and can occur independently of cell division.

Aconitic Acid↗
PubMed1977

Urinary organic acid profiles of Reye's syndrome patients.

The status of mitochondrial functioning in Reye's syndrome was assessed by comparing organic acid profiles from nine pathological urines with those from normal urines. It was found that Reye's syndrome urines have a normal content of succinic, oxaloacetic, aconitic, and citric acids suggesting that the enzymes of the acid cycle are functional. Elevated pyruvate and depressed alpha-ketoglutarate levels were observed. Abnormal urinary constituents detected were salicylic and adipic acids. Presence of the latter indicates that the enzymes of fatty acid beta-oxidation are functional.

Aconitic Acid↗
PubMed1984

Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle.

Considerable variations were found in the in vitro effect of alloxan on mouse liver enzymes associated with the citric acid cycle. The following approximative alloxan concentrations induced 50% inhibition of enzyme activity: 10(-6)M for aconitase, 10(-4)M for NAD-linked isocitrate dehydrogenase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase and fumarase, and 10(-3)M for citrate synthase and NADP-linked isocitrate dehydrogenase. Pyruvate dehydrogenase, succinate dehydrogenase and malate dehydrogenase were not inhibited by 10(-3)M alloxan. The inhibition of aconitase was competitive both when using mouse liver and purified porcine heart enzyme. The Ki values for the purified enzyme in the presence of 5 microM alloxan were 0.22 microM with citrate, 4.0 microM with cis-aconitate and 0.62 microM with isocitrate as substrate. The high sensitivity of aconitase for inhibition by alloxan probably plays a prominent role for the toxic effects of alloxan.

Aconitate Hydratase↗
PubMed1987

Repression and reactivation of the variant surface glycoprotein gene in Trypanosoma brucei.

Rapid repression of variant surface glycoprotein (VSG) synthesis is an early event during the in vitro transformation of Trypanosoma brucei from coated bloodstream forms to uncoated procyclic cells. Repression occurs at the transcriptional level and is triggered by the combined action of two signals: a reduction in temperature from 37 to 27 degrees C and the addition of the citric acid cycle intermediates citrate and cis-aconitate. It is shown that synthesis of VSG mRNA can be reactivated up to 8 h after triggering differentiation by releasing either one or both of the signals. After 30 h repression is irreversible. The results suggest that transformation of bloodstream forms to procyclic cells proceeds through a reversible phase to an irreversible committed state. A reversible repression of VSG mRNA synthesis is also observed upon inhibition of protein synthesis in bloodstream forms at 37 degrees C.

Aconitic Acid↗
PubMed1982

Aconitase from the oyster Crassostrea virginica.

1. The presence of aconitase activity in the oyster. Crassostrea virginica, has been demonstrated. 2. Low levels of activity were found in the different tissues with highest level in digestive diverticular and lowest level in muscle. 3. The conversion of both citrate and iso-citrate to cis-aconitate suggests the presence of an enzyme system capable of utilizing these compounds at a slow but demonstrable rate to give classically expected results. 4. Comparison of the oyster enzyme with aconitase from mammalian tissue indicated great similarity between the two enzyme systems.

Aconitate Hydratase↗
PubMed1996

Aconitase activity in rat liver.

This paper presents data about the subcellular distribution of aconitases in rat liver and some properties of the aconitase activity in cytosol, mitochondria and soluble mitochondrial protein (SMP). The cytosolic and mitochondrial aconitase activity was 64.8% or 61.0% and 20.1% or 19.4% of the total rat liver aconitase activity when cis-aconitate or isocitrate was used as substrate. Aconitase activity of stored SMP and mitochondria with phosphate buffer (pH 7.4) and 0.25 M sucrose (pH 7.4) as isolation medium respectively, was reduced to an equal extent upon exposure to air. Fresh SMP preparations immediately and three hr after isolation had the same aconitase activity. It is concluded that phosphate has no role in the oxidative degradation of mitochondrial aconitase and does not inhibit it. Complete restoration of the decreased mitochondrial aconitase activity to the initial level was achieved with thiomalate and Fe2+ under anaerobic conditions or 60-70% was restored during the long period (60 min) of incubation with exogenous substrate. The aconitase activity of cytosol and mitochondria increased upon exposure to air for 7 1/2 hr. This finding is interpreted to suggest the existence of putative aconitase activity.

Aconitate Hydratase↗