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Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.
Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).
Anaplerotic reactions, a term coined by Hans Kornberg and originating from the Greek ἀνά= 'up' and πληρόω= 'to fill', are chemical reactions that form intermediates of a metabolic pathway. Examples of such are found in the citric acid cycle. In normal function of this cycle for respiration, concentrations of TCA intermediates remain constant; however, many biosynthetic reactions also use these molecules as a substrate. Anaplerosis is the act of replenishing TCA cycle intermediates that have been extracted for biosynthesis.
Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.
Phosphoenolpyruvate carboxykinase is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.
The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.
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Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial (PDK4) is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.
Pyruvate dehydrogenase kinase isoform 2 (PDK2) also known as pyruvate dehydrogenase lipoamide kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase.
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Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene. Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment. This gene has connections to autism.
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Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.
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CDKAL1 is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1. This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.
Phosphoenolpyruvate carboxykinase 2, mitochondrial, is an isozyme of phosphoenolpyruvate carboxykinase that in humans is encoded by the PCK2 gene on chromosome 14. This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described.[provided by RefSeq, Apr 2014]
References
- ↑ Ronnebaum SM, Ilkayeva O, Burgess SC, et al. (October 2006). "A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion". The Journal of Biological Chemistry. 281 (41): 30593–602. doi: 10.1074/jbc.M511908200 . PMID 16912049.
- ↑ Gregory RB, Berry MN (May 1992). "Stimulation by thyroid hormone of coupled respiration and of respiration apparently not coupled to the synthesis of ATP in rat hepatocytes". The Journal of Biological Chemistry. 267 (13): 8903–8. doi: 10.1016/S0021-9258(19)50365-9 . PMID 1577728.
- ↑ Agius L, Tosh D, Peak M (January 1993). "The contribution of pyruvate cycling to loss of 6-3Hglucose during conversion of glucose to glycogen in hepatocytes: effects of insulin, glucose and acinar origin of hepatocytes". The Biochemical Journal. 289 (Pt 1): 255–62. doi:10.1042/bj2890255. PMC 1132158 . PMID 8380985.
- ↑ Pongratz RL, Kibbey RG, Cline GW (2009). "Chapter 24 Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion". Mitochondrial Function, Part B: Mitochondrial Protein Kinases, Protein Phosphatases and Mitochondrial Diseases. Methods in Enzymology. Vol. 457. pp. 425–50. doi:10.1016/S0076-6879(09)05024-1. ISBN 978-0-12-374622-1. PMC 4422111 . PMID 19426882.
- ↑ Guay C, Madiraju SR, Aumais A, Joly E, Prentki M (December 2007). "A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion". The Journal of Biological Chemistry. 282 (49): 35657–65. doi: 10.1074/jbc.M707294200 . PMID 17928289.
- ↑ Ronnebaum SM, Jensen MV, Hohmeier HE, et al. (October 2008). "Silencing of Cytosolic or Mitochondrial Isoforms of Malic Enzyme Has No Effect on Glucose-stimulated Insulin Secretion from Rodent Islets". The Journal of Biological Chemistry. 283 (43): 28909–17. doi: 10.1074/jbc.M804665200 . PMC 2570884 . PMID 18755687.
- ↑ Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJ (June 2009). "Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion". American Journal of Physiology. Endocrinology and Metabolism. 296 (6): E1354–62. doi:10.1152/ajpendo.90836.2008. PMC 2692397 . PMID 19293334.
- ↑ Scaduto RC, Davis EJ (August 1986). "The involvement of pyruvate cycling in the metabolism of aspartate and glycerate by the perfused rat kidney". The Biochemical Journal. 237 (3): 691–8. doi:10.1042/bj2370691. PMC 1147046 . PMID 3800911.