Fatty acids Krebs-citric acid cycle

The Krebs-citric acid cycle is the final common pathway for the oxidation of fuel molecules amino acids, fatty acids and carbohydrates. Most fuel molecules enter the cycle as a breakdown product, acetyl coenzyme A (acetyl CoA), which reacts with oxaloacetate (a four-carbon compound) to produce citrate (a six-carbon compound), which is then converted in a series of enzyme-catalysed steps back to oxaloacetate. In the process, two molecules of carbon dioxide and four energy-rich molecules are given off, and these latter are the precursors of the energy-rich molecule ATP, which is subsequently formed and which acts as the fuel source for all aerobic organisms. 

The citric acid cycle, also known as the TCA (tricarboxylic acid) cycle or Krebs cycle (after its discoverer in 1937), is used to oxidize the pyruvate formed during the glycolytic breakdown of glucose into C02 and H20. It also oxidizes acetyl CoA arising from fatty acid degradation (Topic K2), and amino acid degradation products (Topic M2). In addition, the cycle provides precursors for many biosynthetic pathways. 

Figure 2.7. The complex pathways and processes involved in fat catabolism in vertebrate tissues such as cardiac and skeletal muscles. FFAs arrive at the cell boundary either via VLDL or albumin-associated and enter the cell either by simple diffusion or through transporters. In the cytosol, FFAs are bound by FABPs, which increase the rate and amount of FFA that can be transferred to sites of utilization. Shorter chain FFAs are converted to acetylCoA in peroxisomes longer chain FFAs are directly transferred to mitochondria (via a complex system involving acylcarnitines) as long-chain acylCoA derivatives these enter the /6-oxidation spiral and are released as acetylCoA for entrance into the Krebs or citric acid cycle in the mitochondrial matrix. Fatty acid receptors (FARs) in the nucleus bind to fatty acid response elements (FAREs) and in turn regulate the production of enzymes in their own metabolism. (Modified from Veerkamp and Maatman, 1995.)...

These are the energy producers within the cell. They generate energy in the form of Adenosine Tri-Phosphate (ATP). Generally, the more energy a cell needs, the more mitochondria it contains. Site for Kreb s Citric Acid Cycle Electron transport system and Oxidative Phosphorylation Fatty acid oxidation Amino acid catabolism Interconversion of carbon skeletons. 

Under aerobic conditions, the central metabolic pathway for the oxidation of the carbon skeletons not only of carbohydrates, but also of fatty acids and amino acids, to carbon dioxide is the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle and Krebs cycle. The last-mentioned name is in honor of Sir Adolph Krebs, the biochemist who first proposed the cyclic nature of this pathway in 1937. 

Fig. 2. Various reactions leading to acyl-CoA. The pyruvate dehydrogenase reaction is in fact a sequence of five reactions catalyzed by a three enzyrmes complex. It is the major pathway producing acetyl-CoA, a key molecule in many important metabolic pathways such as the oxidative degradation of glucides (citric acid cycle, also known as Krebs cycle ). Acetyl-CoA is also the starting point for the symthesis of fatty acids, through the fatty acid synthase reaction, which increases the length of the starting fatty acid (R) by two carbon atoms. Most of the other acyl-CoAs are obtained through the acyl-CoA ligase reaction.

It is, however, better known that flavoenzymes (i.e., enzymes utilizing the flavin adenine dinucleotide [FAD FADH2] redox system) mediate the introduction of a,P carbon-carbon double bonds into carboxylic acids and into acetyl Coenzyme A (acetyl CoA) thioesters of long-, medium-, and short-chain fatty acids. In carboxylic acids, such as those of the tricarboxylic acid (citric acid, TCA, or Krebs) cycle (Chapter 11) the oxidation is affected by the enzyme sucdnate dehydrogenase (fumerate reductase— EC 1.3.99.1), which utilizes the cofactor flavin adenine dinucleotide (FAD) The latter is reduced to FADH2 and an ( )-double bond is introduced. The process shown in Scheme 9.105, for the conversion of succinate (1,4-butanedioic acid) to fumerate [(E)-l,4-butenedioic acid], is a fragment of the tricarboxylic acid (citric acid, TCA, or Krebs) cycle (Chapter 11), which is the pathway commonly utilized for oxidative degradation of acetate to carbon dioxide. 

These products are absorbed across the wall of the small intestine into the blood and are transported to cells. Once in the cells, glucose and other monosaccharides, fatty acids, some amino acids, and glycerol enter the mitochondria and feed into a complex series of reactions called the citric acid cycle, or Krebs cycle. The citric acid cycle produces carbon dioxide and other molecules, such as NADH (not to be confused with NADPH) and ATP. This NADH and ATP then move through another set of reactions to produce more ATP and water. 

Acetyl-CoA is oxidized to C02 by the Krebs cycle, also called the tricarboxylic acid cycle or citric acid cycle. The origin of the acetyl-CoA may be pyruvate, fatty acids, amino acids, or the ketone bodies. The Krebs cycle may be considered the terminal oxidative pathway for all foodstuffs. It operates in the mitochondria, its enzymes being located in their matrices. Succinate dehydrogenase is located on the inner mitochondrial membrane and is part of the oxidative phosphorylation enzyme system as well (Chapter 17). The chemical reactions involved are summarized in Figure 18.7. The overall reaction from pyruvate can be represented by Equation (18.5) ... 

Figure 28-7. The metabolism of branched-chain amino acids and odd-chain fatty acids via propionyl-CoA. Propionyl-CoA is converted to D-methylmalonyl-CoA by propionyl-CoA carboxylase. D,L-Methylmalonyl-CoA racemase catalyzes the conversion of D-methylmalonyl-CoA to L-methylmalonyl-CoA. L-methyl malonyl-CoA mutase, an adenosyicobalamin-requiring enzyme, converts L-methylmalonyl-CoA to succinyl-CoA.TCA cycle is citric acid cycle or Kreb s cycle.

The sequence of events known as the Krebs cycle is indeed a cycle ox-aloacetate is both the first reactant and the final product of the metabolic pathway (creating a loop). Because the Krebs cycle is responsible for the ultimate oxidation of metabolic intermediates produced during the metabolism of fats, proteins, and carbohydrates, it is the central mechanism for metabolism in the cell. In the first reaction of the cycle, acetyl CoA condenses with oxaloacetate to form citric acid. Acetyl CoA utilized in this way by the cycle has been produced either via the oxidation of fatty acids, the breakdown of certain amino acids, or the oxidative decarboxylation of pyruvate (a product of glycolysis). The citric acid produced by the condensation of acetyl CoA and oxaloacetate is a tricarboxylic acid containing three car-boxylate groups. (Hence, the Krebs cycle is also referred to as the citric acid cycle or tricarboxyfic acid cycle.)... 

The large amounts of ATP are generated from FADH2, NADH, and acetyl-CoA by subsequent citric acid ( cle (Krebs cycle) and electron transfer chain. It is evident that fatty acid oxidation is a major source of cellular ATP. 

Since pyruvic acid carboxylation via the malic enzyme is the main source of oxaloacetate, slow glycolysis may result in deceleration of the Krebs cycle. The slowing down of glycolysis may result from reduced enzyme activity or from insufficient amounts of substrate the former possibility has been eliminated by the experiments of Chaikoff and his group. These investigators injected lactate, pyruvate, and acetate, and measured their conversion to CO2. They observed that CO2 formation was the same in diabetics as in nondiabetics. Insufficiency of Krebs cycle substrate is also unlikely, because CO2 production, which is derived mainly from the tricarboxylic acid cycle, is unimpaired in diabetes. In addition to being used for citric acid formation, acetyl CoA is also a key building block for fatty acids. 

Krebs Cycle and Fatty Acid Oxidation. A possible role of Krebs cycle intermediates in supporting fatty acid oxidation is now apparent. Complete oxidation to CO2 requires oxalacetate to introduce acetyl CoA into the citric acid cycle. But even the formation of acetoacetate requires the continued generation of ATP to support the activation of fatty acids. The transfer of electrons from fatty acid to oxygen is coupled with phosphate esterification, so that fatty acid oxidation has the theoretical capacity to be self-supporting. In the crude systems that contain all of the essential factors for fatty acid oxidation, fatty acid activation must compete with other reactions for the available ATP, and maximum rates of oxidation occur only when additional ATP is generated through operation of the Krebs cycle. 

Both cofactors are involved in respiratory electron transfer systems (Figure 5.19), for example, in most redox reactions of the citric acid (Krebs) cycle. NAD is most often involved in degradation (catabolism) of sugars, fats, proteins and ethanol, while NADP is involved mainly in biosynthetic (anabolic) reactions, such as synthesis ofmacromolecules, fatty acids and cholesterol. Dinucleotides, in addition of their activities in redox reactions, participate in post-translational modifications of some proteins and other reactions. 

Pyruvate oxidation together with fatty acid oxidation, is the main source of acetyl-CoA, whose main metabolic fate is the breakdown to water and carbon dioxide, through the sequence of reactions known as tricarboxylic acid (TCA) cycle, or Krebs cycle (Krebs) this cycle represents the main contributor of reducing equivalents to the mitochondrial respiratory chaia All of the enzymes of the Krebs citric acid cycle are mitochondrial. According to the majority of authors, they are located in the matrix. 

AcCoA is the building block of fatty acids, polyketides, and mevalonic acid (MVA), a cytosolic precursor of the C5 isoprene units for the biosynthesis of terpenes in the C,5 and Cj series (mind it is different from the MEP pathway, in product, and in cell location). Finally, AcCoA enters the citric acid or Krebs cycle, which leads to several precursors of amino acids. These are oxaloacetic acid, precursor of aspartic acid through transamination (thus toward lysine as a nitrogenated C N linear unit and methionine as a methyl supplier), and 2-oxoglutaric acid, precursor of glutamic acid (and subsequent derivatives such as ornithine as a nitrogenated C N linear unit). All these amino acids are key precursors in the biosynthesis of many alkaloids. 

Krebs cycle (tricarboxylic acid cycle TCA cycle citric acid cycle) A complex and almost universal cycle of reactions in which the acetyl group of acetyl CoA is oxidized to carbon dioxide and water, with the production of large amounts of energy. It is the final common pathway for the oxidation of carbohydrates, fatty acids, and amino acids. It requires oxygen, and in eukaryotes occurs in the mitochondrial matrix. 

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