During gluconeogenesis,<unk>  is involved in the synthesis of phosphoenolpyruvate (PEP) from<unk> .<unk>  is first converted by<unk>  to oxaloacetate (OAA) in the mitochondrion requiring hydrolysis of one molecule of ATP. The OAA is then decarboxylated and simultaneously phosphorylated, which is catalyzed by one of two isoforms of phosphoenolpyruvate carboxykinase (PEPCK) either in the cytosol or in the mitochondria to produce PEP. Under ordinary gluconeogenic conditions, OAA is converted into PEP by mitochondrial PEPCK; the resultant PEP is then transported out of the mitochondrial matrix by an anion transporter carrier system, and converted into glucose by cytosolic gluconeogenic enzymes. However, during starvation when cytosolic NADH concentration is low and mitochrondrial NADH levels are high oxaloacetate can be used as a shuttle of reducing equivalents. As such OAA is converted into malate by mitochondrial malate dehydrogenase (MDH). After export into the cytosol, malate is converted back into OAA, with concomitant reduction of NAD+; OAA is subsequently converted to PEP which is available for gluconeogenesis in the cytosol along with the transported reducing equivalent NADH. Very high levels of<unk>  activity, together with high activities of other gluconeogenic enzymes including PEPCK, fructose-1,6-bisphosphatase and glucose-6-phosphatase in liver and kidney cortex, suggest that a primary role of<unk>  is to participate in gluconeogenesis in these organs. During fasting or starvation when endogenous glucose is required for certain tissues (brain, white blood cells and kidney medulla), expression of<unk>  and other gluconeogenic enzymes is elevated. In rats and mice, alteration of nutrition status has been shown to affect hepatic<unk>  activity. Fasting promotes hepatic glucose production sustained by an increased<unk>  flux, and increases in<unk>  activity and protein concentration; diabetes similarly increases gluconeogenesis through enhanced uptake of substrate and increased flux through liver<unk>  in mice and rats. Similarly to other gluconeogenic enzymes,<unk>  is positively regulated by glucagon and glucocorticoids while negatively regulated by insulin. Further supporting the key role of<unk>  in gluconeogenesis, in dairy cattle, which have hexose absorption ability at adequate nutrition levels,<unk>  and the associated gluconeogenic enzyme PEPCK are markedly elevated during the transition to lactation in proposed support of lactose synthesis for milk production. Aside from the role of<unk>  in gluconeogenesis,<unk>  serves an anaplerotic role (an enzyme catalyzed reaction that can replenish the supply of intermediates in the citric acid cycle) for the tricarboxylic acid cycle (essential to provide oxaloacetate), when intermediates are removed for different biosynthetic purposes. Regulation<unk>  is allosterically regulated by acetyl-CoA, Mg-ATP, and<unk> .
Pyruvate carboxylase
Acyl-CoA dehydrogenase
Aldehyde dehydrogenase
Glutamate dehydrogenase
Phenylalanine hydroxylase
Glycogen phosphorylase isoenzyme BB
Aldehyde oxidase
Xanthine oxidase