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PubMed2005

Exploring intramolecular reactions in complex systems with metadynamics: the case of the malonate anions.

We have determined the optimized structures, relative energies and intramolecular reactions for two anionic forms of malonic acid, anion malonate(-1) (HO(2)CCH(2)CO(2)(-)) and malonate(-2) ((-)O(2)CCH(2)CO(2)(-)). For this purpose we employed accurate quantum chemistry calculations using second-order Möller-Plesset perturbation theory and Density Functional Theory with an aug'-cc-p-VTZ basis set to determine the structures and energies, and a novel metadynamics method based on Car-Parrinello molecular dynamics for the thermal reactions. For both malonates, we found new isomers (keto and enol structures) characterized by CO(2) rotations and intramolecular proton transfers. These proton transfers characterize the keto-enol tautomerism that takes place both in the monoanion and dianion. In all cases, the keto tautomer is the more stable configuration. The metadynamics method allows the system to explore the potential energy surface in a few picoseconds, crossing activation barriers of 20-50 kcal/mol.

Journal Article↗
PubMed1981

Biosynthesis of malonate in roots of soybean seedlings.

Many plants accumulate malonate, but it was shown earlier that malonate does not accumulate as a deadend product of metabolism in soybean (Glycine max v. Hodgson tissues. The metabolism of malonate in the soybean plant at the whole tissue and enzymic level was followed, and the pathway of malonate biosynthesis in young soybean root tissue was shown to be via acetyl-coenzyme A carboxylase.

Journal Article↗
PubMed1998

Malonate decarboxylase of Pseudomonas putida is composed of five subunits.

Two different forms of malonate decarboxylase were purified from Pseudomonas putida. The active form was composed of the five different subunits alpha (60 kDa), beta (33 kDa), gamma (28 kDa), delta (13 kDa), and epsilon (30 kDa) and the inactive form was composed of the four subunits lacking the epsilon subunit. The former catalyzed the decarboxylation of malonate to acetate, but the latter could not, although it retained both activities of acetyl-CoA:malonate CoA transferase and malonyl-CoA decarboxylase. The delta subunit of the active form was acylated by the incubation with [2-14C]malonyl-CoA, but the delta subunit of the inactive form was not labeled. From the above results and the N-terminal amino acid sequence analysis, it was concluded that the epsilon subunit was an essential subunit to function as malonyl-CoA:ACP transacylase, which was an indispensable component of the enzyme for the cyclic decarboxylation of malonate.

Acyl-Carrier Protein S-Malonyltransferase↗
PubMed2001

Tap water and the Malone antegrade continence enema: a safe combination?

PURPOSE: The Malone antegrade continence enema provides independence and improved quality of life in patients with fecal incontinence or intractable constipation. However, isolated reports of fatal hypernatremia after irrigation with normal saline have raised safety concerns about frequent colonic irrigation in children. Significant electrolyte abnormalities have also been reported with hypertonic phosphate and high colonic tap water enemas. Because our patients routinely use tap water for Malone antegrade continence enema irrigations, we examined the safety profile of this practice MATERIALS AND METHODS: In the last 3.5 years 71 patients at our institution have used antegrade tap water enemas for managing fecal incontinence or intractable constipation. Standard serum electrolytes were measured RESULTS: We obtained 101 sets of serum electrolyte measurements in 71 patients at a mean of 8.4 months postoperatively (range 1 to 33). A girl who presented with severe hyponatremia and hypochloremia had not used the Malone antegrade continence enema for several days. The most interesting finding was significantly elevated sodium and chloride in 1 case 6 weeks after surgery that was associated with tap water treated with a home softening system. Electrolytes reverted to normal 1 week after using untreated tap water CONCLUSIONS: We did not detect significant hyponatremia or hypochloremia in any patient using tap water for Malone antegrade continence enema irrigation. Although dangerous electrolyte abnormalities are rare, potential morbidity in those cases warrants periodic evaluation. Due to the elevated sodium content in softened tap water families should be alerted to use untreated tap water for preparing enemas.

Adolescent↗
PubMed1994

Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate.

A potential mechanism of neuronal injury in neurodegenerative diseases is a defect in energy metabolism that may lead to slow excitotoxic neuronal death. Consistent with this possibility, we showed that specific inhibitors of the electron transport chain produce excitotoxic lesions in vivo. In the present study we examined whether agents that improve energy metabolism can block lesions produced by the mitochondrial toxin malonate. Striatal lesions produced by the complex II inhibitor malonate were blocked in a dose-dependent manner by oral pretreatment with coenzyme Q10. Administration of nicotinamide by Alzet pump for 1 week attenuated malonate-induced lesions, but riboflavin had no effect. Administration of nicotinamide intraperitoneally just prior to and following induction of the lesions produced dose-dependent neuroprotection. A combination of coenzyme Q10 with nicotinamide was more effective than either compound alone, as shown by both lesion size and magnetic resonance imaging in vivo. Both coenzyme Q10 and nicotinamide blocked adenosine triphosphate depletions and lactate increases. These results confirm that mitochondrial toxins produce striatal excitotoxic lesions by a mechanism involving energy depletion in vivo. Furthermore, they suggest novel neuroprotective strategies that may be useful in the treatment of both mitochondrial encephalopathies and neurodegenerative diseases.

Animals↗
PubMed1988

Distribution and fate of diethyl malonate and diisopropyl fluorophosphate on pig skin in vitro.

The in vitro distribution and fate of [14C]diethyl malonate and [14C]diisopropyl fluorophosphate were evaluated on normal and heat-treated pig skin. The extent of hydrolysis from the skin surface, skin, and receptor fluid was determined. A significant skin-mediated hydrolysis (15-35% of applied dose) was observed for diethyl malonate in normal skin, but not in heat-treated skin. These results indicated that a heat labile process (e.g., enzymatic hydrolysis) was in part responsible for the degradation of diethyl malonate after topical application to normal skin. Heat treatment tripled the skin penetration of diisopropyl fluorophosphate and reduced the amount of recovered hydrolysis product, diisopropyl phosphoric acid. Enzymatic and spontaneous hydrolysis, as well as impurity, accounted for the presence of degradation product.

Administration, Topical↗
PubMed1998

Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.

Collagenases↗
PubMed1987

Malonate transport in human red blood cells.

Kinetic parameters of [2-14C]malonate uptake by the human erythrocyte membrane have been determined as Km, 24 mM and turnover number, 5 X 10(4) s-1. The translocation of this organic dianion is concentration, pH and temperature dependent. Competitive inhibition of malonate uptake by eosin and inorganic anions, strongly implies that a common route exists for both inorganic anions and organic dianions, namely the anion-exchange Band 3 protein. 14C-Malonate which is nonmetabolized in the erythrocyte, could be a useful probe for monitoring anion-exchange in reconstituted Band 3 systems.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1978

Effect of malonate and maleate on growth and brefeldin A formation in Curvularia lunata.

Malonate exerted a stronger inhibitory effect on brefeldin A production than on mycelia growth in cultures of Curvularia lunata especially at inhibitory levels of 100 to 200 mM. The extent of 200 mM malonate inhibition of growth and brefeldin A production was greater in cultures treated with malonate prior to inoculation than those treated following 5 days after inoculation. Maleate at levels of 40 to 220 mM activated brefeldin A formation in cultures though exerting variable effects on mycelia growth.

Anti-Bacterial Agents↗
PubMed1983

Acylhydrolases from parsley (Petroselinum hortense). Relative distribution and properties of four esterases hydrolyzing malonic acid hemiesters of flavonoid glucosides.

In parsley, malonylated flavonoid glycosides are formed in response to ultraviolet irradiation and accumulate in the vacuoles. Involvement of malonyltransferases, which catalyze the transfer of malonic acid from malonyl-coenzyme A to either flavone/flavonol 7-O-glucosides or flavonol 3-O-glucosides, has been described previously. These enzymes are present in very young leaf buds, and their activities decrease rapidly when leaves begin to unfold, while at the same time esterase activity is developing. The latter enzyme activity continues to increase with tissue age. Four esterases, distinguished by pI's of 3.8, 3.9, 4.0, and 4.05, were purified to apparent homogeneity from parsley leaves and shown to hydrolyze malonic acid hemiesters of flavonoid glucosides. These esterases are unspecific and are best described as one acetyl- and three arylesterases on the basis of inhibition studies by 4-chloromercuribenzoic acid and diisopropyl fluorophosphate. Esterases and malonic acid hemiesters appear to be separated from each other within the parsley leaf cell, and only on disruption of the cells do the respective substrates become available to the enzymes. Involvement of esterases in formation of wound periderm in parsley plants is suggested.

Acyltransferases↗
PubMed1986

Purfication and properties of a specific isoflavone 7-O-glucoside-6''-malonate malonyestrase from roots of chickpea (Cicer arietinum L.).

Protein extracts from roots of chickpea (Cicer arietinum L.) plants contained high esterase activity hydrolyzing malonate hemiesters of isoflavone 7-O-glucosides. Using 5,7-dihydroxy-4'-methoxyisoflavone (biochanin A) 7-O-glucoside-6"-malonate as a substrate, a specific malonylesterase was purified about 700-fold to near homogeneity. The purified enzyme possesses an extremely low enzyme activity with synthetic esterase substrates. Various putative nonspecific esterases, as tested with alpha-naphthylacetate, were removed during enzyme purification. The malonylesterase demonstrated a very high molecular mass in gel chromatography and in sedimentation analyses with sucrose gradients (greater than or equal to 2 X 10(6)). Analytical sodium dodecyl sulfate-polyacrylamide gel electrophoresis pointed to a single subunit of 32,000. The catalyzed reaction showed a pH optimum at 7.5 and a temperature optimum between 30 and 35 degrees C. The apparent Km for biochanin A 7-O-glucoside-6"-malonate was (4.2 +/- 1.2) X 10(-4) M. The malonylesterase was insensitive to the esterase inhibitors eserine and neostigmine (10(-3) M) as well as phenylmethylsulfonyl fluoride, paraoxon, and diisopropylfluorophosphate (10(-4) M). On the other hand enzyme activity was totally inhibited by Hg2+ ions (10(-5) M) and p-hydroxymercuribenzoate (10(-4) M), whereas iodoacetamide (10(-6)-10(-4) M) inhibited only partially. Di- and tricarboxylic acids strongly stimulated enzyme activity at 10(-2) M. These properties indicate that the malonylesterase from chickpea roots greatly differs from other known esterases. The possible biological function of the specific malonylesterase is discussed in relation to isoflavone conjugate metabolism in chickpea.

Carboxylic Acids↗
PubMed1995

Intrastriatal injections of the succinate dehydrogenase inhibitor, malonate, cause a rise in extracellular amino acids that is blocked by MK-801.

The effects of intrastriatal injections of a reversible inhibitor of succinate dehydrogenase, malonate, on the extracellular concentrations of amino acid neurotransmitters were examined using a microdialysis probe that was positioned a fixed distance from an injection cannula. Malonate (2 mumol) caused a 23 +/- 5-fold increase in extracellular glutamate (Glu), a 18 +/- 6-fold increase extracellular gamma-aminobutyric acid (GABA) and a modest increase in extracellular aspartate (Asp, 2.9 +/- 0.8-fold increase). Administration of the NMDA receptor antagonist MK-801 (5 mg/kg) prior to injection of malonate almost completely blocked these increases. This study provides direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular amino acid neurotransmitters and further evidence that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through an excitotoxic mechanism.

Amino Acids↗
PubMed1983

The antitumor complex ethylenediamine platinum (II) malonate: x-ray structure analysis, and studies of its stability in solution.

The anti-tumour compound ethylenediamine platinum (II) malonate has been examined by x-ray crystallography. The molecular structure has a square-planar arrangement around the platinum atom, with the malonate group in a boat conformation and cis to the ethylenediamine group. Solution studies have shown that the malonate ion may be readily displaced from the complex, especially by chloride ion, and at low pH. The implications of this finding for in vivo drug administration are discussed.

Antineoplastic Agents↗
PubMed1995

Chronic treatment with thioctic acid does not protect against malonate toxicity in vivo.

We reported previously that short-term systemic pretreatment with thioctic acid is protective against NMDA and malonate lesions of the striatum. In the current study, we examined the effects of 3 weeks of pretreatment with various doses of thioctic acid (5-60 mg/kg per day) on malonate-induced striatal degeneration in adult rats. In this paradigm, we were unable to demonstrate protection against malonate toxicity. The reasons for the difference in efficacy between subacute and chronic treatment remain to be defined.

Animals↗
PubMed1994

Malonic aciduria.

Three infants with malonic aciduria are reported, one of whom could be studied in detail. All children had severe and progressive encephalopathy with intermittent ketoacidosis and hypoglycemia. One infant died of cardiomyopathy. Biochemical studies revealed that one patient had neither malonyl-CoA decarboxylase nor glutaryl-CoA dehydrogenase deficiencies. This variant of malonic aciduria is different from that of four patients previously reported, both in its clinical and biochemical presentations. The biochemical pathology of this variant malonic aciduria is unknown.

Acidosis↗
PubMed2004

Cortical spreading depression augments kynurenate levels and reduces malonate toxicity in the rat cortex.

Cortical spreading depression (CSD) is characterized by slowly propagating neuronal and astrocytic depolarization, resulting in transient, heightened resistance to subsequent neuronal injury. This study was designed to examine a possible role of the endogenous neuroprotective agent kynurenate (KYNA) in this phenomenon. Unilateral, consecutive CSDs, induced by topical application of 2 M KCl to the cortical surface of adult male rats, resulted in an ipsilateral increase (201-222% compared to controls) in KYNA levels, which was observed in the frontal, parietal and occipital cortex but not in other brain areas. This effect peaked on day 3 after CSD, and KYNA levels returned to normal on day 7. In separate rats, the lesion caused by an intracortical microinjection of the indirect excitotoxin malonate (500 nmol/0.5 microl) on days 1, 3 or 7 after CSD was reduced by 56-75% in the ipsilateral hemisphere. In normal rats, single or multiple injections of the kynurenine 3-hydroxylase inhibitor 4,5-dichlorobenzoylalanine (PNU 156561; 50 mg/kg, i.p.), which results in selective increases in brain KYNA levels, failed to protect cortical neurons against a focal malonate injection. Taken together, these findings indicate that the observed increase in brain KYNA is not responsible for CSD-induced tolerance to malonate-induced neuronal damage.

Animals↗
PubMed2006

Different patterns of axonal damage after intracerebral injection of malonate or AMPA.

White matter damage occurs following stroke and traumatic brain injury. In preclinical studies of potential therapies to reduce acute brain damage, it is important not only to understand the mechanisms by which this damage occurs, but also to employ techniques that fully quantify the extent of damage. In both respects, neurons have previously received greater attention than axons. The aim of the present study was to compare the extent of axonal damage visualised with different immunohistochemical markers following intracerebral injection of either the excitotoxin AMPA or the mitochondrial inhibitor malonate. Adult mice received intrastriatal injection of toxin and 24 h later the amount of white matter damage visualised with either amyloid precursor protein (APP) or neurofilament 200 (NF200) immunohistochemistry. Malonate induced a dose-dependent increase in the extent of axonal damage with either marker. However, AMPA induced a dose-dependent increase in the extent of axonal damage visualised by NF200 immunoreactivity but not by APP immunoreactivity. Malonate and AMPA also differed in their effects on other assessments of white matter integrity and (14)C-2-deoxyglucose autoradiography revealed the two toxins to differ in their initial effects on cerebral metabolism. These data indicate that the ability of commonly-used axonal damage markers to quantify the full extent of white matter damage differs following initial excitotoxicity or mitochondrial inhibition. We also confirmed that the markers reveal different extents of axonal damage in a rat model of focal cerebral ischaemia. Therefore, in preclinical studies designed to assess brain protecting agents, it is advisable to use more than one marker to quantify the true extent of axonal damage.

Amyloid beta-Protein Precursor↗
PubMed2005

Malonate-assisted purification of human caspases.

Caspases have in the past decade become some of the most intensely pursued targets for the design of small-molecule inhibitors. Two significant technological roadblocks to developing caspase-binding molecules are the poor solubility of a subset of the bacterially expressed proteins and the instability of the renatured proteins that results from rapid inactivating autolysis at high protein concentrations. In this report, we present a generalized method of renaturing human caspases and inhibiting the self-proteolytic activity of the enzymes without a need for covalent active-site inhibitors. Our method, which involves blocking the S1 region of the active site with malonate, enables one to inhibit fully the inactivating autolysis in human caspases and increases the yields of renatured active enzyme. It furthermore does not necessitate removal of malonate prior to setting up enzymatic assays since as high as 100-mM concentrations of malonate do not compete efficiently with caspase substrates or larger caspase inhibitors for binding to the active site. The method described in this report simplifies greatly caspase purification and makes it possible to stabilize the enzymes against autolysis without a need for costly, and frequently synthetically challenging, small-molecule inhibitors.

Autolysis↗