Pathways

Citalopram is a selective serotonin reuptake inhibitor used to manage symptoms of depression, anxiety, mood and eating disorders. Off-label indications include but are not limited to: treatment of sexual dysfunction, post-stroke behavioral changes, ethanol abuse, obsessive-compulsive disorder (OCD) in children, and diabetic neuropathy. Citalopram binds selectively to the sodium dependent serotonin transporter and blocks the recycling of serotonin from the synapse. As serotonin accumulates it potentiates serotonergic function of the 5-hydroxytryptamine 1A receptor leading to decreased anxiety and depressive moods. Citalopram is produced as a racemate - a mixture of two stereoisomers: R-citalopram and S-citalopram (escitalopram is the therapeutic active S- enantiomer of citalopram). Citalopram is usually taken orally. The onset of action for depression is about 2 to 4 weeks. However, the full response may take up 8 to 12 weeks.

Citalopram is a selective serotonin reuptake inhibitor used to manage symptoms of depression, anxiety, mood and eating disorders. Off-label indications include but are not limited to: treatment of sexual dysfunction, post-stroke behavioral changes, ethanol abuse, obsessive-compulsive disorder (OCD) in children, and diabetic neuropathy. Citalopram binds selectively to the sodium dependent serotonin transporter and blocks the recycling of serotonin from the synapse. As serotonin accumulates it potentiates serotonergic function of the 5-hydroxytryptamine 1A receptor leading to decreased anxiety and depressive moods. Citalopram is produced as a racemate - a mixture of two stereoisomers: R-citalopram and S-citalopram (escitalopram is the therapeutic active S- enantiomer of citalopram). Citalopram is usually taken orally. The onset of action for depression is about 2 to 4 weeks. However, the full response may take up 8 to 12 weeks.

Citalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

Metabolites of Citalopram are predicted with biotransformer.

The citric acid cycle is the final common oxidative pathway for carbohydrates, fats and amino acids. It is the most important metabolic pathway for the energy supply to the body. TCA is the most important central pathway connecting almost all the individual metabolic pathways. Oxalacetic acid and GTP are catalyzed by phosphoenolypyruvate carboxykinase to form GDP, CO2, and phosphoenolpyruvic acid. This is a single direction reaction occurring outside of the mitochondria. Phosphoenolpyruvic acid then becomes part of the glycolysis/ gluconeogenesis processes outside of the mitochondria which will then produce pyruvic acid that will be trans-located back into the mitochondria. Within the mitochondria, the single direction reaction of pyruvic acid, ATP, and hydrogen carbonate catalyzed by pyruvate carboxylase 1 produces phosphate, ADP, and oxalacetic acid. Pyruvic acid and lipoamide-E are catalyzed by probable pyruvate dehydrogenase E1 component subunit alpha and pyruvate dehydrogenase E1 component subunit beta, mitochondrial to form CO2 and S-acetyldihydrolipoamide-E in a single direction reaction in the mitochondria. S-Acetyldihydrolipoamide-E and CoA are catalyzed by dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex and (R)-lipoic acid to form dihydrolipoamide-E and acetyl-CoA. This is a bi-directional reaction occurring in the mitochondria. Acetyl-CoA is an input compound in the fatty acid biosynthesis and fatty acid elongation in mitochondria sub-pathways, as well as an output compound in the fatty acid metabolism and Val, Leu & Ile degradation sub-pathways. Dihydrolipoamide-E and NAD are catalyzed by dihydrolipoyl dehydrogenase to produce NADH, H+, and lipoamide-E through a bi-directional reaction in the mitochondria. Oxalacetic acid, H2O, and acetyl-CoA are catalyzed by probable ATP-citrate synthase and probable citrate synthase to form CoA and citric acid in a bi-directional reaction in the mitochondria. Oxalacetic acid is an input and output compound in the sub-pathways alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism within the mitochondria. Citric acid is catalyzed by probable cytoplasmic aconitate hydratase to form H2O and cis-aconitic acid, which are then catalyzed again by probable cytoplasmic aconitate hydratase to form isocitric acid. This is a bi-directional reaction in the mitochondria. Isocitric acid is involved in two bi-directional reactions in the mitochondria to form 2- oxoglutaric acid. The first reaction is between isocitric acid and NADP+ catalyzed by isocitrate dehydrogenase [NADP] to produce NADPH, H+, and oxalosuccinic acid. Oxalosuccinic acid is then catalyzed by isocitrate dehydrogenase [NADP] to form CO2 and 2-oxoglutaric acid. The other reaction is between isocitric acid and NAD catalyzed by probable isocitrate dehydrogenase [NAD] subunit alpha, probable isocitrate dehydrogenase [NAD] subunit beta, and magnesium to produce NADH, CO2, H+, and 2-oxoglutaric acid. Oxoglutaric acid is an input compound in the sub-pathway arginine biosynthesis, as well as an input and output compound in the sub-pathways D-Gin & D-Glu metabolism, ascorbate and aldarate metabolism, and alanine, aspartate and glutamate metabolism. In a single direction reaction, oxoglutaric acid and lipoamide-E are catalyzed by 2-oxoglutarate dehydrogenase to form CO2 and S-Succinyldihydrolipoamide-E. S-Succinyldihydrolipoamide-E and CoA are catalyzed by dihydrolipoamide S-Succinyltransferase to produce dihydrolipoamide-E and succinyl-CoA in a bi-directional reaction in the mitochondria. Dihydrolipoamide-E and NAD catalyzed by dihydrolipoyl dehydrogenase produce NADH, H+, and lipoamide-E in a bi-directional reaction. Succinyl-CoA, GDP, and phosphate are catalyzed by succinate--CoA ligase [ADP/GDP-forming] subunit alpha and succinate--CoA ligase [GDP-forming] subunit beta to form CoA, GTP, and succinic acid through a bi-directional reaction. Succinyl-CoA is also an output compound of the sub-pathway Val, Leu & Ile degradation. In another bi-directional reaction, succinic acid and a quinone are catalyzed by succinate dehydrogenase [ubiquinone] flavoprotein subunit and FAD to produce a hydroquinone and fumaric acid. Fumaric acid is an input and output compound in the sub-pathways arginine biosynthesis and tyrosine metabolism within the mitochondria. Fumaric acid and H2O are catalyzed by probable fumarate hydratase to produce L-Malic acid in a bi-directional reaction. L-malic acid and NAD are catalyzed by probable malate dehydrogenase to produce NADH, H+, and oxalacetic acid through a bi-directional reaction.

The citrate lyase activation starts with a 3-dephospho-CoA reacting with ATP and a hydrogen ion through a triphosphoribosyl-dephospho-CoA synthase resulting in a adenine and a 2'-(5'-triphospho-alpha-D-ribosyl)-3'-dephospho-CoA. The latter compound in turn reacts with with a citrate lyase acyl-carrier protein through a apo-citrate lyase phosphoribosyl-dephospho-CoA transferase resulting in the release of a pyrophosphate and a hydrogen ion and a holo citrate lyase acyl-carrier protein.This protein complex can either react with a hydrogen ion and a acetate resulting in the release of a water and an acetyl-holo citrate lyase acyl-carrier protein. The holo acyl-carrier protein creacts with an ATP and an acetate through a citrate lyase synthase resulting in the release of an AMP, a pyrophosphate and an acetyl-holo citrate lyase acyl-ccarrier protein. The holo citrate lyase acyl-carrier protein can also interact with an S-acetyl phosphopantethiene resulting in the release of a 4-phosphopantethiene and an acetyl-holo citrate lyase acyl-carrier protein.

The citrate lyase activation starts with a 3-dephospho-CoA reacting with ATP and a hydrogen ion through a triphosphoribosyl-dephospho-CoA synthase resulting in a adenine and a 2'-(5'-triphospho-alpha-D-ribosyl)-3'-dephospho-CoA. The latter compound in turn reacts with with a citrate lyase acyl-carrier protein through a apo-citrate lyase phosphoribosyl-dephospho-CoA transferase resulting in the release of a pyrophosphate and a hydrogen ion and a holo citrate lyase acyl-carrier protein.This protein complex can either react with a hydrogen ion and a acetate resulting in the release of a water and an acetyl-holo citrate lyase acyl-carrier protein. The holo acyl-carrier protein creacts with an ATP and an acetate through a citrate lyase synthase resulting in the release of an AMP, a pyrophosphate and an acetyl-holo citrate lyase acyl-ccarrier protein. The holo citrate lyase acyl-carrier protein can also interact with an S-acetyl phosphopantethiene resulting in the release of a 4-phosphopantethiene and an acetyl-holo citrate lyase acyl-carrier protein.