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PubMed2004

MetaCyc: a multiorganism database of metabolic pathways and enzymes.

The MetaCyc database (see URL http://MetaCyc.org) is a collection of metabolic pathways and enzymes from a wide variety of organisms, primarily microorganisms and plants. The goal of MetaCyc is to contain a representative sample of each experimentally elucidated pathway, and thereby to catalog the universe of metabolism. MetaCyc also describes reactions, chemical compounds and genes. Many of the pathways and enzymes in MetaCyc contain extensive information, including comments and literature citations. SRI's Pathway Tools software supports querying, visualization and curation of MetaCyc. With its wide breadth and depth of metabolic information, MetaCyc is a valuable resource for a variety of applications. MetaCyc is the reference database of pathways and enzymes that is used in conjunction with SRI's metabolic pathway prediction program to create Pathway/Genome Databases that can be augmented with curation from the scientific literature and published on the world wide web. MetaCyc also serves as a readily accessible comprehensive resource on microbial and plant pathways for genome analysis, basic research, education, metabolic engineering and systems biology. In the past 2 years the data content and the Pathway Tools software used to query, visualize and edit MetaCyc have been expanded significantly. These enhancements are described in this paper.

Biochemical Phenomena↗

PubMed1995

Characterization of the metabolic pathway of 1,25-dihydroxy-16-ene vitamin D3 in rat kidney by on-line high performance liquid chromatography-electrospray tandem mass spectrometry.

1,25-Dihydroxy-16-ene vitamin D3 is a synthetic analog of 1,25-dihydroxyvitamin D3, the most physiologically active metabolite of vitamin D3. The renal metabolism of 1,25-dihydroxy-16-ene vitamin D3 had been studied previously using a perfused rat kidney system [Reddy et al., Bioorg Med Chem Lett 3: 1879-1884, 1993], and its C-24 oxidative metabolic pathway had been found to be different from that of 1,25-dihydroxyvitamin D3 by HPLC. To further delineate the differences between the C-24 oxidative metabolic pathways of 1,25-dihydroxyvitamin D3 and 1,25-dihydroxy-16-ene vitamin D3 in this present study we investigated the C-24 oxidation pathway of 1,25-dihydroxy-16-ene vitamin D3 using a novel detection approach based on on-line capillary liquid chromatography coupled to electrospray tandem mass spectrometry. Two types of tandem mass spectrometric detection were employed to characterize the metabolites in the kidney perfusate: (a) the preliminary screening of metabolites by parent scan, which led to the tentative discovery of the production of 1,23,25-trihydroxy-24-oxo-16-ene vitamin D3, a new metabolite of 1,25-dihydroxy-16-ene vitamin D3, and (b) the pharmacokinetic studies of the substrate, 1,25-dihydroxy-16-ene vitamin D3 and its metabolites by multiple reaction monitoring. In the latter, the mass spectrometric sensitivity for quantification was found to be about 20-fold better than UV detection. The current work concluded that the C-24 oxidative metabolic pathway of 1,25-dihydroxy-16-ene vitamin D3 closely mimicked that of its natural counterpart. Furthermore, the use of mass spectrometry permitted the clearance rate of the starting substrate to be studied at a more physiological level (ng/mL or submicromolar level), which had not been possible previously by HPLC-UV detection.

Animals↗

PubMed2001

Metabolism of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) by human liver microsomes: characterization of metabolic pathways and of cytochrome P450 isoforms involved.

Metabolic fate of DDB and identification of P450 isozymes involved in the metabolism of DDB were investigated in human liver microsomes. DDB was rapidly metabolized to five different metabolites, and the structures of each metabolite were characterized based on UV, mass, and NMR spectral analyses. The major metabolic pathways of DDB in human liver microsomes were identified as O-demethylation of the carboxymethyl moiety (M4) and demethylenation of the methylenedioxyphenyl group (M2). The intramolecular lactonization between the hydroxyl group at the C6 and carboxymethyl group at the C2' of M2 resulted in the generation of M5, which was either hydrolyzed to its hydrolyzed derivative (M1) or further metabolized to the O-demethylated derivative (M3). The interconversion of M1, M2, and M5 took place nonenzymatically depending on the solvent condition. M5 was predominantly detected at the acidic condition, whereas M1 was preferentially detected at the basic environment. Cytochrome P450 (P450) isoform(s) involved in the metabolism of DDB was identified using several in vitro approaches. Chemical inhibition using isoform-selective P450 inhibitors, correlation of DDB metabolites formation with several isoform-specific P450 activities in a panel of liver microsomes, metabolism by microsomes derived from P450 cDNA-expressed B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-P450 antibodies collectively indicated that CYP1A2, CYP2C9, and CYP3A4 are responsible for the metabolism of DDB. O-Dealkylation of the carboxymethyl group was preferentially catalyzed by CYP1A2, whereas demethylenation of the methylenedioxyphenyl moiety was catalyzed by CYP3A4 and CYP2C9.

Antibodies↗

PubMed1977

Specific metabolic pathway in vitro of pinazepam and diazepam by liver microsomal enzymes of different animal species.

The metabolic pathway of Pinazepam and Diazepam in vitro was studied with rat, guinea pig and dog liver microsomes using a chromatographic and spectrophotometric technique. Two main pathways were observed, N1-dealkylation and C3-hydroxylation. N1-dealkylation was shown to be the predominant reaction for Pinazepam in all the animal species studied, while C3-hydroxylation was the major metabolic pathway for Diazepam in the rat. No oxazepam was found when Pinazepam and Diazepam were incubated with liver microsomes.

Animals↗

PubMed2000

Metabolic pathways for cytotoxic end product formation from glutamate- and aspartate-containing peptides by Porphyromonas gingivalis.

Metabolic pathways involved in the formation of cytotoxic end products by Porphyromonas gingivalis were studied. The washed cells of P. gingivalis ATCC 33277 utilized peptides but not single amino acids. Since glutamate and aspartate moieties in the peptides were consumed most intensively, a dipeptide of glutamate or aspartate was then tested as a metabolic substrate of P. gingivalis. P. gingivalis cells metabolized glutamylglutamate to butyrate, propionate, acetate, and ammonia, and they metabolized aspartylaspartate to butyrate, succinate, acetate, and ammonia. Based on the detection of metabolic enzymes in the cell extracts and stoichiometric calculations (carbon recovery and oxidation/reduction ratio) during dipeptide degradation, the following metabolic pathways were proposed. Incorporated glutamylglutamate and aspartylaspartate are hydrolyzed to glutamate and aspartate, respectively, by dipeptidase. Glutamate is deaminated and oxidized to succinyl-coenzyme A (CoA) by glutamate dehydrogenase and 2-oxoglutarate oxidoreductase. Aspartate is deaminated into fumarate by aspartate ammonia-lyase and then reduced to succinyl-CoA by fumarate reductase and acyl-CoA:acetate CoA-transferase or oxidized to acetyl-CoA by a sequential reaction of fumarase, malate dehydrogenase, oxaloacetate decarboxylase, and pyruvate oxidoreductase. The succinyl-CoA is reduced to butyryl-CoA by a series of enzymes, including succinate-semialdehyde dehydrogenase, 4-hydroxybutyrate dehydrogenase, and butyryl-CoA oxidoreductase. A part of succinyl-CoA could be converted to propionyl-CoA through the reactions initiated by methylmalonyl-CoA mutase. The butyryl- and propionyl-CoAs thus formed could then be converted into acetyl-CoA by acyl-CoA:acetate CoA-transferase with the formation of corresponding cytotoxic end products, butyrate and propionate. The formed acetyl-CoA could then be metabolized further to acetate.

Acetic Acid↗

PubMed2000

Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation.

A potential new metabolic pathway of melatonin biotransformation is described in this investigation. Melatonin was found to directly scavenge hydrogen peroxide (H(2)O(2)) to form N(1)-acetyl-N(2)-formyl-5-methoxykynuramine and, thereafter this compound could be enzymatically converted to N(1)-acetyl-5-methoxykynuramine by catalase. The structures of these kynuramines were identified using proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. This is the first report to reveal a possible physiological association between melatonin, H(2)O(2), catalase, and kynuramines. Melatonin scavenges H(2)O(2) in a concentration-dependent manner. This reaction appears to exhibit two distinguishable phases. In the rapid reaction phase, the interaction between melatonin and H(2)O(2) reaches equilibrium rapidly (within 5 s). The rate constant for this phase was calculated to be 2.3 x 10(6) M(-1)s(-1). Thereafter, the relative equilibrium of melatonin and H(2)O(2) was sustained for roughly 1 h, at which time the content of H(2)O(2) decreased gradually over a several hour period, identified as the slow reaction phase. These observations suggest that melatonin, a ubiquitously distributed small nonenzymatic molecule, might serve to directly detoxify H(2)O(2) in living organisms. H(2)O(2) and melatonin are present in all subcellular compartments; thus, presumably, one important function of melatonin may be complementary in function to catalase and glutathione peroxidase in keeping intracellular H(2)O(2) concentrations at steady-state levels.

Catalase↗

PubMed1986

Glucoside formation as a novel metabolic pathway of pantothenic acid in the dog.

Metabolism of pantothenic acid (PaA) in beagle dogs was investigated. The dogs excreted 12.3% of the dose in the urine within 24 hr after a single oral administration of [3H]PaA (3 mg/kg). High performance liquid chromatographic analysis of the urine showed the presence of unchanged vitamin and a major metabolite, which accounted for 60.2 and 39.8% of the urinary radioactivity respectively. Although the metabolite was hydrolyzed by treatment with beta-glucuronidase or acid phosphatase, it was found that this hydrolysis resulted from the actions of beta-glucosidase contained as a contaminant in these enzyme preparations. beta-Glucosidase completely hydrolyzed the metabolite to generate PaA and glucose. The metabolite was isolated and subjected to GC/MS and NMR analyses. It was identical to synthetic PaA beta-glucoside, 4'-O-(beta-D-glucopyranosyl)-D-pantothenic acid. It was shown by the use of dog liver microsomes that PaA underwent beta-glucosidation in the presence of uridine diphosphate glucose (UDPG). It is proposed that beta-glucosidation by UDP-glucosyltransferase is a novel metabolic pathway of PaA in the dog.

Animals↗

PubMed2005

Alignment of metabolic pathways.

MOTIVATION: Several genome-scale efforts are underway to reconstruct metabolic networks for a variety of organisms. As the resulting data accumulates, the need for analysis tools increases. A notable requirement is a pathway alignment finder that enables both the detection of conserved metabolic pathways among different species as well as divergent metabolic pathways within a species. When comparing two pathways, the tool should be powerful enough to take into account both the pathway topology as well as the nodes' labels (e.g. the enzymes they denote), and allow flexibility by matching similar--rather than identical--pathways. RESULTS: MetaPathwayHunter is a pathway alignment tool that, given a query pathway and a collection of pathways, finds and reports all approximate occurrences of the query in the collection, ranked by similarity and statistical significance. It is based on a novel, efficient graph matching algorithm that extends the functionality of known techniques. The program also supports a visualization interface with which the alignment of two homologous pathways can be graphically displayed. We employed this tool to study the similarities and differences in the metabolic networks of the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae, as represented in highly curated databases. We reaffirmed that most known metabolic pathways common to both the species are conserved. Furthermore, we discovered a few intriguing relationships between pathways that provide insight into the evolution of metabolic pathways. We conclude with a description of biologically meaningful meta-queries, demonstrating the power and flexibility of our new tool in the analysis of metabolic pathways.

Animals↗

PubMed1991

Integrated genetic databases in the study of neuropsychiatric diseases: inborn errors of cerebral metabolic pathways?

1. Genetic databases are an expanding and readily accessible repository of information on the mapping and sequencing of the human genome, and that of other model organisms. The integration and application of this information to neuropsychiatric disease is illustrated using neuroendocrine and neuropharmacologic data, computerized and other genetic databases. 2. This computer-assisted integrated approach to knowledge structures permits the rapid generation of hypotheses, the prompt identification of candidate gene loci, an explanation for genetic heterogeneity, and strategies for the use of potential linked markers. 3. Results using this integrated search strategy demonstrate that over 30 candidate loci for neuropsychiatric disease have currently been mapped in man (spread over 14 chromosomes in the human genome), and that at least 6 homologous loci have been mapped in mouse. 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11-13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway, i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region. 5. Parallels are suggested between inborn errors of metabolic pathways in the somatic endocrine system (using insulin-dependent diabetes mellitus as a paradigm) and the neurotransmitter and hormonal systems within the brain. 6. A subset of neuropsychiatric disorders may thus be viewed as inborn errors of cerebral metabolic pathways primarily affecting the biogenic amine pathways.

Animals↗

PubMed2005

[Metabolic pathways of dipfluzine in rats].

AIM: To investigate the metabolic pathways of dipfluzine in rats. METHODS: After an oral dose of dipfluzine (80 mg x kg(-1)) to rats, urine was collected for 12 h. The metabolites of dipfluzine in urine were chromatographed and identified by LC/DAD/MS methods. RESULTS: In the rat urine, there were 1-(4-fluorophenyl)-4-piperazinylbutanone and its glucuronide, 4-hydroxybenzophenone and its glucuronide, 4-fluoro-gamma-hydroxybenzenebutanoic acid and its glucuronide and sulfate, diphenylmethanol and its glucuronide, dipfluzine, and benzophenone. CONCLUSION: In rats, dipfluzine was mainly metabolized in the pathways of N-desalkylation at 1- and 4-positions of piperazine ring. Some of metabolites were further conjugated with glucuronic acid and/or sulfuric acid.

Animals↗

PubMed2003

The metabolic pathway of salicylic acid rather than of chlorogenic acid is involved in the stress-induced flowering of Pharbitis nil.

We examined the involvement of chlorogenic acid (CGA) and salicylic acid (SA) in the stress-induced flowering of Pharbitis nil (synonym Ipomoea nil). The incorporation efficiency of exogenously applied CGA and the deactivation rate of incorporated CGA were determined in cotyledons by high-performance liquid chromatography. The assay plants could not incorporate a sufficient amount of CGA via roots. The perfusion technique by which the assay solution was forced into the plant from the cut end of the hypocotyl improved the efficiency of CGA incorporation. However, no flower-inducing activity was detected, indicating that CGA was not involved in flowering. It was concluded that the close correlation between CGA content and flowering response is merely coincidence or a parallelism. Flowering under long-day conditions induced by low-temperature stress was completely inhibited by aminooxyacetic acid (AOA), an inhibitor of phenylalanine ammonialyase. The flower-inhibiting effect of AOA was nullified by co-applied t-cinnamic acid and by benzoic acid. This indicates that the metabolic pathway from t-cinnamic acid to SA via benzoic acid is involved in the stress-induced flowering. The results indicate that the metabolic pathway of SA is involved in the stress-induced flowering of P. nil not the metabolic pathway of CGA.

Aminooxyacetic Acid↗

PubMed2002

Analysis of dibenzothiophene metabolic pathway in Mycobacterium strain G3.

The dibenzothiophene (DBT) metabolic pathway in Mycobacterium strain G3, which is classified as a desulfurizing microorganism with the 4S pathway, was analyzed. 2-Hydroxybiphenyl (HBP), which is an end metabolite in the DBT desulfurization reaction, and 2-methoxybiphenyl (MBP) were found in the reaction mixture, and the methoxylation pathway from HBP to MBP was clarified. Although the substrate in the methoxylation reaction was HBP, there was no relationship between expression of the methoxylation activity and that of the desulfurization activity. Then, 4,6-dimethyl DBT, 4,6-diethyl DBT and benzo[b]naphtho[2,1-d]thiophene were metabolized to their methoxy forms via the desulfurization pathway. We established the methoxylation pathway in Mycobacterium G3.

Journal Article↗

PubMed2003

PathMiner: predicting metabolic pathways by heuristic search.

MOTIVATION: Automated methods for biochemical pathway inference are becoming increasingly important for understanding biological processes in living and synthetic systems. With the availability of data on complete genomes and increasing information about enzyme-catalyzed biochemistry it is becoming feasible to approach this problem computationally. In this paper we present PathMiner, a system for automatic metabolic pathway inference. PathMiner predicts metabolic routes by reasoning over transformations using chemical and biological information. RESULTS: We build a biochemical state-space using data from known enzyme-catalyzed transformations in Ligand, including, 2917 unique transformations between 3890 different compounds. To predict metabolic pathways we explore this state-space by developing an informed search algorithm. For this purpose we develop a chemically motivated heuristic to guide the search. Since the algorithm does not depend on predefined pathways, it can efficiently identify plausible routes using known biochemical transformations.

Algorithms↗

PubMed1997

Induction of the cholesterol metabolic pathway regulates the farnesylation of RAS in embryonic chick heart cells: a new role for ras in regulating the expression of muscarinic receptors and G proteins.

We propose a novel mechanism for the regulation of the processing of Ras and demonstrate a new function for Ras in regulating the expression of cardiac autonomic receptors and their associated G proteins. We have demonstrated previously that induction of endogenous cholesterol synthesis in cultured cardiac myocytes resulted in a coordinated increase in expression of muscarinic receptors, the G protein alpha-subunit, G-alphai2, and the inward rectifying K+ channel, GIRK1. These changes in gene expression were associated with a marked increase in the response of heart cells to parasympathetic stimulation. In this study, we demonstrate that the induction of the cholesterol metabolic pathway regulates Ras processing and that Ras regulates expression of G-alphai2. We show that in primary cultured myocytes most of the RAS is localized to the cytoplasm in an unfarnesylated form. Induction of the cholesterol metabolic pathway results in increased farnesylation and membrane association of RAS. Studies of Ras mutants expressed in cultured heart cells demonstrate that activation of Ras by induction of the cholesterol metabolic pathway results in increased expression of G-alphai2 mRNA. Hence farnesylation of Ras is a regulatable process that plays a novel role in the control of second messenger pathways.

Animals↗

PubMed1988

Starch Biosynthesis in Developing Wheat Grain : Evidence against the Direct Involvement of Triose Phosphates in the Metabolic Pathway.

We have used (13)C-labeled sugars and nuclear magnetic resonance (NMR) spectrometry to study the metabolic pathway of starch biosynthesis in developing wheat grain (Triticum aestivum cv Mardler). Our aim was to examine the extent of redistribution of (13)C between carbons atoms 1 and 6 of [1-(13)C] or [6-(13)C]glucose (or fructose) incorporated into starch, and hence provide evidence for or against the involvement of triose phosphates in the metabolic pathway. Starch synthesis in the endosperm tissue was studied in two experimental systems. First, the (13)C sugars were supplied to isolated endosperm tissue incubated in vitro, and second the (13)C sugars were supplied in vivo to the intact plant. The (13)C starch produced by the endosperm tissue of the grain was isolated and enzymically degraded to glucose using amyloglucosidase, and the distribution of (13)C in all glucosyl carbons was quantified by (13)C-NMR spectrometry. In all of the experiments, irrespective of the incubation time or incubation conditions, there was a similar pattern of partial (between 15 and 20%) redistribution of label between carbons 1 and 6 of glucose recovered from starch. There was no detectable increase over background (13)C incidence in carbons 2 to 5. Within each experiment, the same pattern of partial redistribution of label was found in the glucosyl and fructosyl moieties of sucrose extracted from the tissue. Since it is unlikely that sucrose is present in the amyloplast, we suggest that the observed redistribution of label occurred in the cytosolic compartment of the endosperm cells and that both sucrose and starch are synthesized from a common pool of intermediates, such as hexose phosphate. We suggest that redistribution of label occurs via a cytosolic pathway cycle involving conversion of hexose phosphate to triose phosphate, interconversion of triose phosphate by triose phosphate isomerase, and resynthesis of hexose phosphate in the cytosol. A further round of triose phosphate interconversion in the amyloplast could not be detected. These data seriously weaken the argument for the selective uptake of triose phosphates by the amyloplast as part of the pathway of starch biosynthesis from sucrose in plant storage tissues. Instead, we suggest that a hexose phosphate such as glucose 1-phosphate, glucose 6-phosphate, or fructose 6-phosphate is the most likely candidate for entry into the amyloplast. A pathway of starch biosynthesis is presented, which is consistent with our data and with the current information on the intracellular distribution of enzymes in plant storage tissues.

Journal Article↗

PubMed1994

Structure identifiability in metabolic pathways: parameter estimation in models based on the power-law formalism.

An important step in understanding a metabolic pathway is to identify its structure, in terms of the flow of material and information. In pursuing this goal, the available information for a given system is usually obtained from experiments in vitro and comes from different sources. Frequently, the final set of regulatory signals acting in the system in vivo is unclear, and some kind of test is needed on the intact system. Besides defining an appropriate experimental approach, identification of the regulatory pattern needs a theoretical framework in which the different experimental measurements can be evaluated and a final picture can be agreed on. Mathematical approaches based on sensitivity coefficients provide a useful tool for addressing this problem. Within this framework, the appropriate parameters are related to both the structure of the reaction network and the signals that regulate the target system. Thus the identification of the regulatory structure can be related to the estimation of the appropriate set of parameters. In pursuing this goal, we will show the limitations of using steady-state measurements and the usefulness of using dynamic data. We suggest a way to test the regulatory pattern in a given metabolic pathway by combining both kinds of data, and we show, by using a reference system, the potential of the method suggested.

Metabolism↗

PubMed2006

Metabolic pathway analysis for rational design of L-methionine production by Escherichia coli and Corynebacterium glutamicum.

Metabolic pathway analysis was carried out to predict the metabolic potential of Corynebacterium glutamicum and Escherichia coli for the production of L-methionine. Based on detailed stoichiometric models for these organisms, this allowed the calculation of the theoretically optimal methionine yield and related metabolic fluxes for various scenarios involving different mutants and process conditions. The theoretical optimal methionine yield on the substrates glucose, sulfate and ammonia for the wildtype of C. glutamicum is 0.49 (C-mol) (C-mol)(-1), whereas the E. coli wildtype exhibits an even higher potential of 0.52 (C-mol) (C-mol)(-1). Both strains showed completely different optimal flux distributions. C. glutamicum has a high flux through the pentose phosphate pathway (PPP), whereas the TCA cycle flux is very low. Additionally, it recruits a metabolic cycle, which involves 2-oxoglutarate and glutamate. In contrast, E. coli does minimize the flux through the PPP, and the flux through the TCA cycle is high. The improved potential of the E. coli wildtype is due to its membrane-bound transhydrogenase and its glycine cleavage system as shown by additional simulations with theoretical mutants. A key point for maximizing methionine yield is the choice of the sulfur source. Replacing sulfate by thiosulfate or sulfide increased the maximal theoretical yield in C. glutamicum up to 0.68 (C-mol) (C-mol)(-1). A further increase is possible by the application of additional C1 sources. The highest theoretical potential was obtained for C. glutamicum applying methanethiol as combined source for C1 carbon and sulfur (0.91 (C-mol) (C-mol)(-1)). Substrate requirement for maintenance purposes reduces theoretical methionine yields. In the case of sulfide used as sulfur source a maintenance requirement of 9.2 mmol ATP g(-1) h(-1), as was observed under stress conditions, would reduce the maximum theoretical yield from 67.8% to 47% at a methionine production rate of 0.65 mmol g(-1) h(-1). The enormous capability of both organisms encourages the development of biotechnological methionine production, whereby the use of metabolic pathway analysis, as shown, provides valuable advice for future strategies in strain and process improvement.

Bacterial Proteins↗

PubMed2002

Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia.

Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.

Adult↗