Tricarboxylic Acid Cycle

The tricarboxylic acid (TCA) cycle (also known as the citric acid cycle) is located in the mitochondrial matrix and is a common metabolic pathway for all fuels. It is responsible for the production of the majority of the reduced coenzymes used for the generation of ATP in the electron transfer chain. It also plays a central role in the interconversion of

Glucose

Hexokinase

ATP ADP

Glucose-6-phosphatase

Glycogen

Glucose-6-P

Phosphohexose isomerase

— Hexose monophosphate NADP+— NADPH

Fructose-6-P

Pentose phosphate

Phosphofructokinase ADP

Phosphohexose isomerase

Fructose-6-P

Aldolase

Phosphofructokinase ADP

Nucleotides

Glyceraldehyde-3-P

Glyceraldehyde-3-P Dehydrogenase NADH + H+

Nucleotides

Aldolase

DNA /RNA

Dihydroxyacetone-P —

Glyceraldehyde-3-P

Glycerol-3-P

Fats (lipogenesis)

Glyceraldehyde-3-P Dehydrogenase NADH + H+

1,3-Biphosphoglycerate

ADP ATP

(via 2 intermediates)

Phosphoenolpyruvate

Pyruvate kinase ^P

Enolpyruvate

Nonenzymic

Lactate

Nonenzymic

NAD+

NADH+H+

Pyruvate

NAD+

NADH+H+

Phosphoenolpyruvate

Enolpyruvate

Pyruvate

GDP GTP

ADP ATP

GDP GTP

Oxaloacetate

ADP ATP

TCA cycle net = 2 NADH = 6 ATP + net 2 ATP Figure 3 Glycolysis and its interactions with other metabolic pathways.

fuels and metabolites. The TCA cycle participates in gluconeogenesis from amino acids and lactate during fasting between meals and longer term in starvation. TCA cycle intermediates are the source of most of the nonessential amino acids, such as aspartate and glutamate. It is also involved in the conversion of carbohydrates to fat for storage after a carbohydrate-rich meal.

Pyruvate (3C) from glycolysis is oxidatively dec-arboxylated to acetyl-CoA (2C) in the mitochondria, catalyzed by the multienzyme complex pyruvate dehydrogenase and the coenzyme A (Co-ASH):

Pyruvate dehydrogenase requires several coenzymes derived from vitamins, including vitamin B1 or thiamine, niacin (NAD), riboflavin (FAD), and pantothenic acid (a component of CoA). Deficiencies in any of these vitamins can affect energy metabolism, as

Pyruvate

-CoASH 'Pyruvate dehydrogenase

Fatty acids Ketone bodies

-CoASH 'Pyruvate dehydrogenase

Ketogenic amino acid

Ketogenic amino acid

NAD+

Oxaloacetate [4C]

Malate dehydrogenase

Citrate [6C]

NAD+

Malate dehydrogenase

Malate [4C]

\Aconitase Isocitrate

Malate [4C]

A Fumarase

Isocitrate dehydrogenase

Fumarate [4C]

Succinate FAD \

Ketoglutarate [SC] CoASH

dehydrogenase FADH —N

Succinate [4C]

CoASH

CoASH

GTP GDP+P

Succinyl CoA synthetase

Ketoglutarate dehydrogenase

Ketoglutarate dehydrogenase

GTP GDP+P

Succinyl CoA synthetase

Figure 4 The oxidative decarboxylation of pyruvate and the tricarboxylic acid cycle.

evidenced by the increased cellular pyruvate and cardiac and skeletal muscle weakness in beriberi caused by thiamine deficiency. Pyruvate dehydrogenase catalyzes a central reaction in carbohydrate metabolism, and therefore its activity is regulated by both allosteric and covalent mechanisms.

Acetyl-CoA can be produced from pyruvate but also from fatty acids released from fat stores and from amino acids released from proteolysis of protein tissue, which can be converted to acetyl-CoA or cycle intermediates. In the first of the eight enzymatic reactions, acetyl-CoA (2C) combines with oxaloacetate (4C), forming citrate (6C) and releasing the CoA for further reactions with pyruvate to acetyl-CoA. A cycle of reactions follows in which two molecules of CO2 are released and three molecules of NADH + H+ and one of FADH2 are produced along with one molecule of GTP (equivalent to ATP). At the end of the cycle, oxaloacetate is regenerated and able to react again with another molecule of acetyl-CoA, and so the cycle continues (Figure 4).

In the electron transfer chain, each NADH + H+ yields approximately 3 ATP and FADH2 yields 2

ATP. Thus, each rotation of the TCA cycle produces approximately 12 ATP (3 NADH + H+« 9 ATP + 1 FADH2 « 2 ATP + 1 GTP). Because two molecules of acetyl-CoA are formed from one glucose molecule, the TCA cycle rotates twice for each molecule of glucose respired, producing a net of 24 ATP (Table 1).

Breaking Bulimia

Breaking Bulimia

We have all been there: turning to the refrigerator if feeling lonely or bored or indulging in seconds or thirds if strained. But if you suffer from bulimia, the from time to time urge to overeat is more like an obsession.

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