Nursing - 6

Tricarboxylic acid cycle and Gluconeogenesis

Metabolic fate of pyruvate

* Pyruvate is transported to the mitochondria via a special pyruvate transporter where it can be transformed into: 1.oxaloacetic acid.(CO2 fixation):

* It provides extra 6 molecules of ATP formed by

oxidation of NADH by the ETC.

In animals:

The formation of acetyl CoA from pyruvate is a

key irreversible step in metabolism because

they are unable to convert acetyl CoA into

glucose.

Pyruvate as a junction point Pyruvate occupies an important junction between

various metabolic pathways. It may be decarboxylated to acetyl-CoA which enters the TCA cycle, or may be utilized for fatty acid synthesis.

Pyruvate may be carboxylated to oxaloacetate which is used for gluconeogenesis.

Pyruvate dehydrogenase step is the committed step towards oxidation of glucose.

Citric acid cycle (CAC)

or Tricarboxylic Acid Cycle (TCA)

or Krebs Cycle

Definition:

It is a series of reactions in mitochondria, that

brings about the catabolism of acetyl residues,

liberating hydrogen equivalents which upon

oxidation, leads to the release of energy.

Functions of the Citric Acid Cycle 1. It is the final common oxidation pathway that

oxidizes acetyl CoA to CO2.

2. It is the source of reduced coenzymes that provide the substrate for the respiratory chain.

3. It acts as a link between catabolic and anabolic pathway (amphibolic role).

4. It provides precursors for synthesis of amino acids and nucleotides.

5. Components of the cycle have direct or indirect controlling effects on key enzymes of other pathways.

Total ATP produced from complete oxidation of

one molecule of glucose during glycolysis,

oxidative decarboxylation and CAC :

Glycolysis G 2PA 8 ATP

Oxidative decarboxylation 2PA 2 acetyl CoA 6 ATP

(2 NADH + H+ ×3)

Oxidation of 2 acetyl CoA in CAC (12 ATP ×2) 24 ATP

38 ATP

1- Fluorocitrate inhibits aconitase.

2- Mercury and arsenite inhibit pyruvate and α–

ketoglutarate dehydrogenase complex.

3- Malonic acid inhibits succinic acid

dehydrogenase.

Inhibitors of CAC:

MalonicMalonic acidacid

fluorocitratefluorocitrate

ArseniteArsenite and mercuryand mercury

Inhibitors of CACInhibitors of CAC

Definition:

Synthesis of glucose (and/or glycogen) from non-carbohydrate

precursors such as, lactate, glucogenic amino acids, glycerol and

propionate.

Some tissues such as the brain, RBCs, kidney medulla, lens and

cornea of the eyes, testis, and exercising muscle require a continuous

supply of glucose as a metabolic fuel. Liver glycogen can meet these

needs for only 10-18 hours in the absence of dietary intake of CHO.

During prolonged fasting, hepatic glycogen stores are depleted and

glucose is formed from, non- carbohydrate precursors.

Gluconeogenic key enzymes Glycolytic key enzymes

Glucose-6-phosphatase Glucokinase, hexokinase 1-

Fructose-1,6-bisphosphatase Phosphofructo kinase-1 2-

Pyruvate carboxylase Pyruvate Kinase 3-

Phosphoenolpyruvate carboxykinase

Site: The major site of gluconeogenesis is the liver (90%); it can also occur in the cortex of the kidney (10%). It occurs mainly in the cytoplasm and partly in the mitochondria. Steps: It is nearly the reversal of glycolysis except for the three irreversible kinases as follows:-

Succinyl CoA

The gluconeogenic substrates give directly or indirectly pyruvate, oxaloacetate or any intermediates of glycolysis or C.A.C.

They include the following:

1. Lactate:

It diffuses out of active skeletal muscle or red cells, into the blood and is carried to the liver, where it is converted to glucose by gluconeogenic pathway .

* 6 high energy phosphate bonds are spent during synthesis of glucose from 2 molecules of pyruvate:

2 ATP are utilized by pyruvate carboxylase.

2 GTP are utilized by PEP carboxykinase [2GTP= 2ATP]

2 ATP are utilized for reversal of phosphoglycerate kinase.

2. Glucogenic amino acids:

They give pyruvate or oxaloacetate directly or indirectly by giving intermediates of C.A.C as - ketoglutarate, succinyl CoA, and fumarate. All a.a. can give glucose except leucine (pure ketogenic).

After 18 hours fasting, proteins are considered as one of the main sources of glucose.

3. Glycerol:

It is mobilized from adipose tissues. Two molecules of glycerol are utilized for production of one molecule of glucose in liver and kidney in fasting or low CHO diet. Glycerol can not be utilized in adipose tissue which lacks glycerol kinase.

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