Citric acid cycle intermediates serve as substrates for biosynthetic processes

The Citric Acid Cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism!!! See also [1], Krebs cycle importance, and Major metabolic pathways converging on the citric acid cycle.

Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle. Acetyl-CoA cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion).

Fatty acid synthesis and the production of cholesterol

The cytosolic acetyl-CoA is used for fatty acid synthesis and the production of cholesterol. can, in turn, be used to synthesize the steroid hormones, bile salts, and .

• Fatty acid synthesis
• Biosynthesis of cholesterol
• Steroid Hormones and their receptors
• Vitamin D receptor
• Steroids

The carbon skeletons of many non-essential amino acids are made from citric acid cycle intermediates

The carbon skeletons of many non-essential amino acids are made from citric acid cycle intermediates. To turn them into amino acids the alpha keto-acids formed from the citric acid cycle intermediates have to acquire their amino groups from glutamate in a transamination reaction, in which pyridoxal phosphate is a cofactor. In this reaction the glutamate is converted into alpha-ketoglutarate, which is a citric acid cycle intermediate. The intermediates that can provide the carbon skeletons for amino acid synthesis are oxaloacetate which forms aspartate and asparagine; and alpha-ketoglutarate which forms glutamine, proline, and arginine.

• Alpha-Ketoglutarates: glutamate, glutamine, proline, arginine
• Oxaloacetate/aspartate: lysine, asparagine, methionine, threonine, and isoleucine

Bases in DNA and RNA

Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the purines that are used as the bases in DNA and RNA, as well as in ATP, AMP, GTP, NAD, FAD and CoA.

The pyrimidines are partly assembled from aspartate (derived from oxaloacetate). The pyrimidines, thymine, cytosine and uracil, form the complementary bases to the purine bases in DNA and RNA, and are also components of CTP, UMP, UDP and UTP.

Porphyrins

The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, . . These molecules are an important component of the hemeproteins, such as hemoglobin, myoglobin and various cytochromes.

Gluconeogenesis

During gluconeogenesis mitochondrial oxaloacetate is reduced to malate which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then decarboxylated to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase, which is the rate limiting step in the conversion of nearly all the gluconeogenic precursors (such as the glucogenic amino acids and lactate) into glucose by the liver and kidney.

Catabolism of amino acids, Citric Acid Cycle intermediates and Gluconeogenesis

1) , cysteine, glycine, serine, tryptophan, threonine =>

2) Tryptophan, threonine, phenylalanine, tyrosine, isoleucine, leucine, lysine =>

3) Arginine, histidine, glutamine, proline => glutamate =>

4) Threonine, methionine, isoleucine, valine => 4C chain (CoA excluded)

5) Tyrosine, phenylalanine, aspartate =>

6) Aspartate, asparagine => =>

[by Phosphoenolpyruvate carboxykinase] (PEP) => ... =>

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. When the infusion of citric acid cycle intermediates exceeds cataplerotic demand (such as for aspartate or glutamate synthesis), some of them can be extracted to the gluconeogenesis pathway, in the liver and kidneys, through phosphoenolpyruvate carboxykinase, and converted to free glucose.