241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
The pyruvate dehydrogenase complex catalyzes the overallconversion of pyruvate to acetyl-CoA and CO(2), and thereby linksthe glycolytic pathway to the tricarboxylic cycle
Glycolysis is the process of converting glucose into pyruvate and generating small amounts of ATP (energy) and NADH (reducing power). It is a central pathway that produces important precursor metabolites: six-carbon compounds of glucose-6P and fructose-6P and three-carbon compounds of glycerone-P, glyceraldehyde-3P, glycerate-3P, phosphoenolpyruvate, and pyruvate [MD:M00001]. Acetyl-CoA, another important precursor metabolite, is produced by oxidative decarboxylation of pyruvate [MD:M00307]. When the enzyme genes of this pathway are examined in completely sequenced genomes, the reaction steps of three-carbon compounds from glycerone-P to pyruvate form a conserved core module [MD:M00002], which is found in almost all organisms and which sometimes contains operon structures in bacterial genomes. Gluconeogenesis is a synthesis pathway of glucose from noncarbohydrate precursors. It is essentially a reversal of glycolysis with minor variations of alternative paths [MD:M00003].
The citrate cycle (TCA cycle, Krebs cycle) is an important aerobic pathway for the final steps of the oxidation of carbohydrates and fatty acids. The cycle starts with acetyl-CoA, the activated form of acetate, derived from glycolysis and pyruvate oxidation for carbohydrates and from beta oxidation of fatty acids. The two-carbon acetyl group in acetyl-CoA is transferred to the four-carbon compound of oxaloacetate to form the six-carbon compound of citrate. In a series of reactions two carbons in citrate are oxidized to CO2 and the reaction pathway supplies NADH for use in the oxidative phosphorylation and other metabolic processes. The pathway also supplies important precursor metabolites including 2-oxoglutarate. At the end of the cycle the remaining four-carbon part is transformed back to oxaloacetate. According to the genome sequence data, many organisms seem to lack genes for the full cycle [MD:M00009], but contain genes for specific segments [MD:M00010 M00011].
Carbon metabolism is the most basic aspect of life. This map presents an overall view of central carbon metabolism, where the number of carbons is shown for each compound denoted by a circle, excluding a cofactor (CoA, CoM, THF, or THMPT) that is replaced by an asterisk. The map contains carbon utilization pathways of glycolysis (map00010), pentose phosphate pathway (map00030), and citrate cycle (map00020), and six known carbon fixation pathways (map00710 and map00720) as well as some pathways of methane metabolism (map00680). The six carbon fixation pathways are: (1) reductive pentose phosphate cycle (Calvin cycle) in plants and cyanobacteria that perform oxygenic photosynthesis, (2) reductive citrate cycle in photosynthetic green sulfur bacteria and some chemolithoautotrophs, (3) 3-hydroxypropionate bi-cycle in photosynthetic green nonsulfur bacteria, two variants of 4-hydroxybutyrate pathways in Crenarchaeota called (4) hydroxypropionate-hydroxybutyrate cycle and (5) dicarboxylate-hydroxybutyrate cycle, and (6) reductive acetyl-CoA pathway in methanogenic bacteria.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.
Glucagon is conventionally regarded as a counterregulatory hormone for insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Glucagon also stimulates hepatic mitochondrial beta-oxidation to supply energy for glucose production. Glucagon performs its main effect via activation of adenylate cyclase. The adenylate-cyclase-derived cAMP activates protein kinase A (PKA), which then phosphorylates downstream targets, such as cAMP response element binding protein (CREB) and the bifunctional enzyme 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (one of the isoforms being PFK/FBPase 1, encoded by PFKFB1).
Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.
The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003)
Glyoxylate is generated in the course of glycine and hydroxyproline catabolism and can be converted to oxalate. In humans, this process takes place in the liver. Defects in two enzymes of glyoxylate metabolism, alanine:glyoxylate aminotransferase (AGXT) and glycerate dehydrogenase/glyoxylate reductase (GRHPR), are associated with pathogenic overproduction of oxalate (Danpure 2005). The reactions that interconvert glycine, glycolate, and glyoxylate and convert glyoxylate to oxalate have been characterized in molecular detail in humans. A reaction sequence for the conversion of hydroxyproline to glyoxylate has been inferred from studies of partially purified extracts of rat and bovine liver but the enzymes involved in the corresponding human reactions have not been identified
Vitamin A (retinol) can be metabolised into active retinoid metabolites that function either as a chromophore in vision or in regulating gene expression transcriptionally and post-transcriptionally. Genes regulated by retinoids are essential for reproduction, embryonic development, growth, and multiple processes in the adult, including energy balance, neurogenesis, and the immune response. The retinoid used as a cofactor in the visual cycle is 11-cis-retinal (11cRAL). The non-visual cycle effects of retinol are mediated by retinoic acid (RA), generated by two-step conversion from retinol (Napoli 2012). All-trans-retinoic acid (atRA) is the major activated metabolite of retinol. An isomer, 9-cis-retinoic acid (9cRA) has biological activity, but has not been detected in vivo, except in the pancreas. An alternative route involves BCO1 cleavage of carotenoids into retinal, which is then reduced into retinol in the intestine (Harrison 2012). The two isomers of RA serve as ligands for retinoic acid receptors (RAR) that regulate gene expression. (Das et al. 2014). RA is catabolised to oxidised metabolites such as 4-hydroxy-, 18-hydroxy- or 4-oxo-RA by CYP family enzymes, these metabolites then becoming substrates for Phase II conjugation enzymes (Ross & Zolfaghari 2011)
Pyruvate sits at an intersection of key pathways of energy metabolism. It is the end product of glycolysis and the starting point for gluconeogenesis, and can be generated by transamination of alanine. It can be converted by the pyruvate dehydrogenase complex to acetyl CoA (Reed and Hackert 1990) which can enter the TCA cycle or serve as the starting point for the syntheses of long chain fatty acids, steroids, and ketone bodies depending on the tissue and metabolic state in which it is formed. It also plays a central role in balancing the energy needs of various tissues in the body. Under conditions in which oxygen supply is limiting, e.g., in exercising muscle, or in the absence of mitochondria, e.g., in red blood cells, re-oxidation of NADH produced by glycolysis cannot be coupled to generation of ATP. Instead, re-oxidation is coupled to the reduction of pyruvate to lactate. This lactate is released into the blood, and is taken up primarily by the liver, where it is oxidized to pyruvate and can be used for gluconeogenesis (Cori 1981)
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