Gluconeogenesis: Difference between revisions

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Alexander Berchansky

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 <StructureSection load='2y3i' size='350' side='right' scene='' caption='Human phosphoglycerate kinase complex with phosphoglyceric acid, ADP (stick model) AlF4-, Cl- and Mg+2 ions (green) (PDB code [[2y3i]])'>
-'''Under development!'''
+Gluconeogenesis ([https://en.wikipedia.org/wiki/Gluconeogenesis]) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. In humans the main gluconeogenic precursors are lactate, <scene name='92/925544/Cv/1'>glycerol</scene> (which is a part of the triglyceride molecule), alanine and glutamine. Other glucogenic amino acids and all [[Citric Acid Cycle]] intermediates (through conversion to oxaloacetate) can also function as substrates for gluconeogenesis. See also [[Cori cycle]] and [[Glyoxylate cycle]].
-Gluconeogenesis is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. In humans the main gluconeogenic precursors are lactate, <scene name='92/925544/Cv/1'>glycerol</scene> (which is a part of the triglyceride molecule), alanine and glutamine. Other glucogenic amino acids and all citric acid cycle intermediates (through conversion to oxaloacetate) can also function as substrates for gluconeogenesis.
 <scene name='39/392339/Cv1/10'>Lactate</scene> is transported back to the liver where it is converted into <scene name='39/392339/Cv1/11'>pyruvate</scene> by the [[Cori cycle]] using the enzyme [[lactate dehydrogenase]]. <scene name='Lactate_Dehydrogenase/Cv/4'>Interconversion of pyruvate and lactate acid</scene>. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.
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 ,3-bisphosphoglycerate + ADP ⇌ glycerate 3-phosphate + ATP
-Like all kinases it is a transferase. PGK is a major enzyme used in glycolysis, in the first ATP-generating step of the glycolytic pathway. In gluconeogenesis, the reaction catalyzed by PGK proceeds in the opposite direction, generating ADP and 3-phosphoglycerate (3-PG)
+Like all kinases it is a transferase. PGK is a major enzyme used in glycolysis, in the first ATP-generating step of the glycolytic pathway. In gluconeogenesis, the reaction catalyzed by PGK proceeds in the opposite direction, generating ADP and 3-phosphoglycerate (3-PG).
+'''Catabolism of amino acids, [[Citric Acid Cycle]] and Gluconeogenesis'''
+) <scene name='92/925544/Cv/2'>Alanine</scene>, cysteine, glycine, serine, tryptophan, threonine => <scene name='39/392339/Cv1/11'>pyruvate</scene>
+) Tryptophan, threonine, phenylalanine, tyrosine, isoleucine, leucine, lysine => <scene name='43/430893/Cv/2'>Acetyl-CoA</scene>
+) Arginine, histidine, glutamine, proline => glutamate => <scene name='43/430893/Cv/8'>α-Ketoglutarate</scene>
+) Threonine, methionine, isoleucine, valine => <scene name='43/430893/Cv/9'>Succinyl-CoA</scene> 4C chain (CoA excluded)
+) Tyrosine, phenylalanine, aspartate => <scene name='43/430893/Cv/11'>Fumarate</scene>
+) Aspartate, asparagine => <scene name='43/430893/Cv/3'>Oxaloacetate</scene> =>
+[by [[Phosphoenolpyruvate carboxykinase]]] <scene name='39/392339/Cv1/8'>phosphoenolpyruvate</scene> (PEP) => ... => <scene name='39/392339/Cv/3'>Glucose</scene>
+The location of the enzyme that links these two parts of gluconeogenesis by converting oxaloacetate to PEP – [[PEP carboxykinase]] (PEPCK) – is variable by species: it can be found entirely within the mitochondria, entirely within the cytosol, or dispersed evenly between the two, as it is in humans. ''E. coli'' GTP-driven PEPCK <scene name='54/540171/Cv/9'>active site</scene> is located in a pocket at the enzyme surface<ref>PMID:11851336</ref>. Water molecules are shown as red spheres.
+'''Fatty acids'''
+Odd-chain fatty acids can be oxidized to yield <scene name='43/430893/Cv/2'>Acetyl-CoA</scene> and <scene name='92/925544/Cv/4'>Propionyl-CoA</scene>, the latter serving as a precursor to <scene name='43/430893/Cv/9'>Succinyl-CoA</scene>, which can be converted to <scene name='39/392339/Cv1/11'>pyruvate</scene> and enter into gluconeogenesis. In contrast, even-chain fatty acids are oxidized to yield only acetyl-CoA, whose entry into gluconeogenesis requires the presence of a [[glyoxylate cycle]] (also known as glyoxylate shunt) to produce four-carbon dicarboxylic acid precursors.
+'''Pathway'''
+'''1)''' Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by [[pyruvate carboxylase]]. This enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in the liver) and inhibited by high levels of ADP and glucose.
+[[Pyruvate carboxylase]]: <scene name='39/392339/Cv1/11'>Pyruvate</scene> => <scene name='43/430893/Cv/3'>Oxaloacetate</scene>
+'''2)''' Oxaloacetate is reduced to <scene name='43/430893/Cv/12'>malate</scene> using NADH, a step required for its transportation out of the mitochondria.
+'''3)''' Malate is oxidized to oxaloacetate using NAD+ in the cytosol, where the remaining steps of gluconeogenesis take place.
+'''4)''' <scene name='43/430893/Cv/3'>Oxaloacetate</scene> is decarboxylated and then phosphorylated to form <scene name='39/392339/Cv1/8'>phosphoenolpyruvate</scene> using the enzyme [[PEPCK]]. A molecule of GTP is hydrolyzed to GDP during this reaction.
+The next steps in the reaction are the same as reversed glycolysis. However, [[fructose 1,6-bisphosphatase]] converts <scene name='39/392339/Cv1/2'>fructose 1,6-bisphosphate</scene> to <scene name='92/925544/Cv/5'>fructose 6-phosphate</scene>, using one water molecule and releasing one phosphate (in glycolysis, phosphofructokinase 1 converts F6P and ATP to F1,6BP and ADP). This is also the rate-limiting step of gluconeogenesis.
+<scene name='39/392339/Cv/4'>Glucose-6-phosphate</scene> is formed from <scene name='39/392339/Cv1/1'>fructose-6-phosphate</scene> by [[phosphoglucoisomerase]] (the reverse of step 2 in glycolysis). Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose.
+The final gluconeogenesis, the formation of glucose, occurs in the lumen of the endoplasmic reticulum, where <scene name='39/392339/Cv/4'>glucose-6-phosphate</scene> is hydrolyzed by glucose-6-phosphatase to produce <scene name='39/392339/Cv/3'>glucose</scene> and release an inorganic phosphate.
 </StructureSection>
 == References ==
 <references/>