During the Citric Acid Cycle What Happens to Acetyl Coa

During the Citric Acid Cycle What Happens to Acetyl Coa

Metabolic pathway

Overview of the citric acid bike

The
citric acrid bicycle
(CAC)—too known equally the
Krebs cycle
or the
TCA cycle (tricarboxylic acrid cycle)
[ane]
[2]—is a series of chemic reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (every bit opposed to organisms that ferment) to generate free energy, either by anaerobic respiration or aerobic respiration. In addition, the wheel provides precursors of certain amino acids, likewise as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that information technology was one of the earliest components of metabolism and may have originated abiogenically.[iii]
[4]
Even though it is branded as a ‘cycle’, it is non necessary for metabolites to follow only 1 specific road; at to the lowest degree three culling segments of the citric acid bicycle have been recognized.[5]

The name of this metabolic pathway is derived from the citric acrid (a tricarboxylic acid, ofttimes chosen citrate, every bit the ionized form predominates at biological pH[6]) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the course of acetyl-CoA) and water, reduces NAD+
to NADH, releasing carbon dioxide. The NADH generated past the citric acid bicycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the course of ATP.

In eukaryotic cells, the citric acid wheel occurs in the matrix of the mitochondrion. In prokaryotic cells, such as leaner, which lack mitochondria, the citric acrid cycle reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the cell’s surface (plasma membrane) rather than the inner membrane of the mitochondrion. The overall yield of energy-containing compounds from the citric acid wheel is 3 NADH, one FADHtwo, and one GTP.[vii]

Discovery

[edit]

Several of the components and reactions of the citric acid cycle were established in the 1930s past the research of Albert Szent-Györgyi, who received the Nobel Prize in Physiology or Medicine in 1937 specifically for his discoveries pertaining to fumaric acrid, a cardinal component of the bicycle.[8]
He fabricated this discovery past studying pigeon chest muscle. Because this tissue maintains its oxidative capacity well afterward breaking down in the Latapie mill and releasing in aqueous solutions, chest muscle of the pigeon was very well qualified for the report of oxidative reactions.[9]
The citric acid wheel itself was finally identified in 1937 by Hans Adolf Krebs and William Arthur Johnson while at the University of Sheffield,[x]
for which the former received the Nobel Prize for Physiology or Medicine in 1953, and for whom the bicycle is sometimes named the “Krebs bicycle”.[11]

Overview

[edit]

Structural diagram of acetyl-CoA: The portion in bluish, on the left, is the acetyl group; the portion in black is coenzyme A.

The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize acetate (a 2 carbon molecule), in the form of acetyl-CoA, into two molecules each of carbon dioxide and water. Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The reactions of the cycle also catechumen three equivalents of nicotinamide adenine dinucleotide (NAD+) into three equivalents of reduced NAD+
(NADH), one equivalent of flavin adenine dinucleotide (FAD) into ane equivalent of FADH2, and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (Pi) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH2
generated by the citric acid bike are, in turn, used by the oxidative phosphorylation pathway to generate energy-rich ATP.

I of the primary sources of acetyl-CoA is from the breakup of sugars by glycolysis which yield pyruvate that in plough is decarboxylated by the pyruvate dehydrogenase circuitous generating acetyl-CoA co-ordinate to the following reaction scheme:



CH3C(=O)C(=O)O


pyruvate



+ HSCoA + NAD+



CH3C(=O)SCoA

acetyl-CoA



+ NADH + CO2

The production of this reaction, acetyl-CoA, is the starting point for the citric acrid bike. Acetyl-CoA may too be obtained from the oxidation of fatty acids. Below is a schematic outline of the cycle:

  • The citric acrid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to course a six-carbon compound (citrate).
  • The citrate so goes through a serial of chemic transformations, losing ii carboxyl groups every bit COii. The carbons lost as COtwo
    originate from what was oxaloacetate, non straight from acetyl-CoA. The carbons donated past acetyl-CoA become part of the oxaloacetate carbon backbone afterwards the beginning turn of the citric acid wheel. Loss of the acetyl-CoA-donated carbons as COii
    requires several turns of the citric acid bicycle. All the same, because of the role of the citric acid cycle in anabolism, they might not be lost, since many citric acid cycle intermediates are likewise used as precursors for the biosynthesis of other molecules.[12]
  • Most of the electrons made bachelor past the oxidative steps of the wheel are transferred to NAD+, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced. The citric acid cycle includes a serial of oxidation reduction reaction in mitochondria.[
    description needed
    ]

    [13]
  • In add-on, electrons from the succinate oxidation step are transferred start to the FAD cofactor of succinate dehydrogenase, reducing it to FADHtwo, and eventually to ubiquinone (Q) in the mitochondrial membrane, reducing information technology to ubiquinol (QHii) which is a substrate of the electron transfer chain at the level of Circuitous III.
  • For every NADH and FADH2
    that are produced in the citric acrid cycle, 2.5 and 1.5 ATP molecules are generated in oxidative phosphorylation, respectively.
  • At the end of each wheel, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps

[edit]

There are 10 basic steps in the citric acid cycle, as outlined below. The cycle is continuously supplied with new carbon in the grade of acetyl-CoA, entering at step 0 in the table.[14]

Reaction type Substrates Enzyme Products Comment
0 / 10 Aldol condensation Oxaloacetate + Acetyl CoA + HiiO Citrate synthase Citrate + CoA-SH irreversible, extends the 4C oxaloacetate to a 6C molecule
ane Aridity Citrate Aconitase cis-Aconitate + H2O reversible isomerisation
two Hydration cis-Aconitate + H2O Isocitrate
3 Oxidation Isocitrate + NAD+ Isocitrate dehydrogenase Oxalosuccinate + NADH + H
+
generates NADH (equivalent of ii.v ATP)
4 Decarboxylation Oxalosuccinate α-Ketoglutarate + CO2 rate-limiting, irreversible stage, generates a 5C molecule
five Oxidative
decarboxylation
α-Ketoglutarate + NAD+
+ CoA-SH
α-Ketoglutarate
dehydrogenase, Thiamine pyrophosphate, Lipoic acid, Mg++,transsuccinytase
Succinyl-CoA + NADH + H
+
+ COtwo
irreversible stage, generates NADH (equivalent of 2.v ATP), regenerates the 4C concatenation (CoA excluded)
6 substrate-level
phosphorylation
Succinyl-CoA + Gdp + Pi Succinyl-CoA synthetase Succinate + CoA-SH + GTP or ADP→ATP instead of GDP→GTP,[xv]
generates ane ATP or equivalent.
Condensation reaction of GDP + Pi
and hydrolysis of succinyl-CoA involve the H2O needed for balanced equation.
7 Oxidation Succinate + ubiquinone (Q) Succinate dehydrogenase Fumarate + ubiquinol (QHtwo) uses FAD equally a prosthetic group (FAD→FADH2
in the starting time step of the reaction) in the enzyme.[xv]

These two electrons are afterward transferred to QHtwo
during Complex Ii of the ETC, where they generate the equivalent of 1.5 ATP
8 Hydration Fumarate + HtwoO Fumarase L-Malate Hydration of C-C double bond
ix Oxidation L-Malate + NAD+ Malate dehydrogenase Oxaloacetate + NADH + H+ reversible (in fact, equilibrium favors malate), generates NADH (equivalent of 2.5 ATP)
10 / 0 Aldol condensation Oxaloacetate + Acetyl CoA + HiiO Citrate synthase Citrate + CoA-SH This is the same equally step 0 and restarts the cycle. The reaction is irreversible and extends the 4C oxaloacetate to a 6C molecule

Two carbon atoms are oxidized to COtwo, the free energy from these reactions is transferred to other metabolic processes through GTP (or ATP), and as electrons in NADH and QH2. The NADH generated in the citric acid wheel may afterward be oxidized (donate its electrons) to drive ATP synthesis in a type of process called oxidative phosphorylation.[6]
FADH2
is covalently fastened to succinate dehydrogenase, an enzyme which functions both in the CAC and the mitochondrial electron transport concatenation in oxidative phosphorylation. FADH2, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron ship chain.[15]

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: ane that produces GTP from Gdp, and another that produces ATP from ADP.[16]
Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase).[14]
Several of the enzymes in the cycle may be loosely associated in a multienzyme poly peptide complex within the mitochondrial matrix.[17]

The GTP that is formed past GDP-forming succinyl-CoA synthetase may exist utilized by nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).[fifteen]

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Products

[edit]

Products of the commencement turn of the cycle are one GTP (or ATP), three NADH, one FADH2
and two CO2.

Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the finish of two cycles, the products are: two GTP, vi NADH, two FADH2, and four CO2.[18]

Clarification Reactants Products
The sum of all reactions in the citric acid cycle is: Acetyl-CoA + iii NAD+
+ FAD + Gdp + Pi
+ 2 H2O
→ CoA-SH + 3 NADH + FADHtwo
+ three H+
+ GTP + 2 CO2
Combining the reactions occurring during the pyruvate oxidation with those occurring during the citric acid wheel, the following overall pyruvate oxidation reaction is obtained: Pyruvate ion + iv NAD+
+ FAD + GDP + Pi
+ 2 HiiO
→ iv NADH + FADH2
+ iv H+
+ GTP + 3 CO2
Combining the to a higher place reaction with the ones occurring in the form of glycolysis, the following overall glucose oxidation reaction (excluding reactions in the respiratory chain) is obtained: Glucose + ten NAD+
+ 2 FAD + 2 ADP + two Gross domestic product + 4 Pi
+ 2 H2O
→ ten NADH + 2 FADH2
+ 10 H+
+ two ATP + 2 GTP + half-dozen COii

The higher up reactions are balanced if Pi
represents the H2PO4

ion, ADP and GDP the ADP2−
and Gdptwo−
ions, respectively, and ATP and GTP the ATP3−
and GTP3−
ions, respectively.

The full number of ATP molecules obtained after complete oxidation of 1 glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be betwixt 30 and 38.[19]

Efficiency

[edit]

The theoretical maximum yield of ATP through oxidation of 1 molecule of glucose in glycolysis, citric acid bike, and oxidative phosphorylation is 38 (assuming iii molar equivalents of ATP per equivalent NADH and 2 ATP per FADH2). In eukaryotes, two equivalents of NADH and four equivalents of ATP are generated in glycolysis, which takes place in the cytoplasm. Transport of two of these equivalents of NADH into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and FADHtwo
to less than the theoretical maximum yield.[19]
The observed yields are, therefore, closer to ~2.v ATP per NADH and ~1.5 ATP per FADH2, farther reducing the total net production of ATP to approximately 30.[20]
An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.[21]

Variation

[edit]

While the citric acrid cycle is in full general highly conserved, in that location is pregnant variability in the enzymes found in different taxa[22]
(annotation that the diagrams on this folio are specific to the mammalian pathway variant).

Some differences exist between eukaryotes and prokaryotes. The conversion of D-threo-isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD+-dependent EC 1.i.1.41, while prokaryotes employ the NADP+-dependent EC ane.i.1.42.[23]
Similarly, the conversion of (Due south)-malate to oxaloacetate is catalyzed in eukaryotes past the NAD+-dependent EC 1.1.one.37, while nigh prokaryotes apply a quinone-dependent enzyme, EC 1.one.5.iv.[24]

A stride with significant variability is the conversion of succinyl-CoA to succinate. Nearly organisms employ EC 6.2.1.5, succinate–CoA ligase (ADP-forming) (despite its proper name, the enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (Gdp-forming) (EC half dozen.2.1.4) also operates. The level of utilization of each isoform is tissue dependent.[25]
In some acetate-producing leaner, such equally
Acetobacter aceti, an entirely dissimilar enzyme catalyzes this conversion – EC 2.8.3.18, succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA wheel with acetate metabolism in these organisms.[26]
Some leaner, such as
Helicobacter pylori, use all the same another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase (EC 2.8.3.5).[27]

Some variability also exists at the previous step – the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD+-dependent 2-oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin-dependent ii-oxoglutarate synthase (EC one.two.7.three).[28]
Other organisms, including obligately autotrophic and methanotrophic leaner and archaea, bypass succinyl-CoA entirely, and catechumen 2-oxoglutarate to succinate via succinate semialdehyde, using EC 4.i.1.71, ii-oxoglutarate decarboxylase, and EC one.2.1.79, succinate-semialdehyde dehydrogenase.[29]

In cancer, there are substantial metabolic derangements that occur to ensure the proliferation of tumor cells, and consequently metabolites tin accumulate which serve to facilitate tumorigenesis, dubbed oncometabolites.[30]
Amongst the best characterized oncometabolites is two-hydroxyglutarate which is produced through a heterozygous gain-of-office mutation (specifically a neomorphic one) in isocitrate dehydrogenase (IDH) (which under normal circumstances catalyzes the oxidation of isocitrate to oxalosuccinate, which then spontaneously decarboxylates to blastoff-ketoglutarate, as discussed higher up; in this case an additional reduction step occurs after the formation of alpha-ketoglutarate via NADPH to yield 2-hydroxyglutarate), and hence IDH is considered an oncogene. Under physiological atmospheric condition, 2-hydroxyglutarate is a modest product of several metabolic pathways as an fault merely readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes (L2HGDH and D2HGDH)[31]
merely does not have a known physiologic role in mammalian cells; of notation, in cancer, 2-hydroxyglutarate is likely a terminal metabolite every bit isotope labelling experiments of colorectal cancer cell lines show that its conversion back to blastoff-ketoglutarate is too low to measure.[32]
In cancer, 2-hydroxyglutarate serves as a competitive inhibitor for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent dioxygenases. This mutation results in several important changes to the metabolism of the cell. For ane thing, because there is an actress NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of blastoff-ketoglutarate available to the prison cell. In item, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. Information technology is produced largely via the pentose phosphate pathway in the cytoplasm. The depletion of NADPH results in increased oxidative stress within the cell as information technology is a required cofactor in the production of GSH, and this oxidative stress can result in DNA damage. At that place are also changes on the genetic and epigenetic level through the office of histone lysine demethylases (KDMs) and 10-eleven translocation (TET) enzymes; ordinarily TETs hydroxylate v-methylcytosines to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be washed and there is hence hypermethylation of the jail cell’s DNA, serving to promote epithelial-mesenchymal transition (EMT) and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group.[33]
Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of hypoxia-inducible factor alpha, which is necessary to promote degradation of the latter (as under atmospheric condition of low oxygen there volition not be acceptable substrate for hydroxylation). This results in a pseudohypoxic phenotype in the cancer jail cell that promotes angiogenesis, metabolic reprogramming, jail cell growth, and migration.

Regulation

[edit]

Allosteric regulation by metabolites. The regulation of the citric acid cycle is largely determined past product inhibition and substrate availability. If the bike were permitted to run unchecked, large amounts of metabolic energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of forerunner NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid bike with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and as well citrate synthase. Acetyl-coA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase. When tested in vitro with TCA enzymes,
ATP
inhibits citrate synthase and α-ketoglutarate dehydrogenase; however, ATP levels do not modify more than 10% in vivo between rest and vigorous exercise. There is no known allosteric mechanism that can account for big changes in reaction rate from an allosteric effector whose concentration changes less than ten%.[6]

Citrate
is used for feedback inhibition, as information technology inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses germination of fructose one,6-bisphosphate, a forerunner of pyruvate. This prevents a abiding loftier rate of flux when at that place is an accumulation of citrate and a decrease in substrate for the enzyme.

Regulation past calcium. Calcium is as well used every bit a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach upwards to the tens of micromolar levels during cellular activation.[34]
Information technology activates pyruvate dehydrogenase phosphatase which in plow activates the pyruvate dehydrogenase complex. Calcium also activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.[35]
This increases the reaction charge per unit of many of the steps in the cycle, and therefore increases flux throughout the pathway.

Transcriptional regulation. Recent work has demonstrated an important link betwixt intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is synthesized constitutively, and hydroxylation of at least i of ii critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl four-hydroxylases. Fumarate and succinate have been identified as strong inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.[36]

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Major metabolic pathways converging on the citric acid cycle

[edit]

Several catabolic pathways converge on the citric acid wheel. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions, from the Greek meaning to “fill up”. These increment the corporeality of acetyl CoA that the cycle is able to carry, increasing the mitochondrion’due south capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the wheel are termed “cataplerotic” reactions.

In this section and in the next, the citric acid cycle intermediates are indicated in
italics
to distinguish them from other substrates and end-products.

Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix. Here they can be oxidized and combined with coenzyme A to grade CO2,
acetyl-CoA, and NADH, as in the normal cycle.[37]

However, information technology is as well possible for pyruvate to be carboxylated past pyruvate carboxylase to class
oxaloacetate. This latter reaction “fills upwardly” the amount of
oxaloacetate
in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to metabolize
acetyl-CoA
when the tissue’s free energy needs (e.g. in musculus) are suddenly increased by activity.[38]

In the citric acid bicycle all the intermediates (eastward.g.
citrate,
iso-citrate,
alpha-ketoglutarate,
succinate,
fumarate,
malate, and
oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore ways that that additional amount is retained within the bicycle, increasing all the other intermediates as one is converted into the other. Hence the addition of whatsoever ane of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic result. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of
oxaloacetate
available to combine with
acetyl-CoA
to course
citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the prison cell.[38]

Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fat acids, is the only fuel to enter the citric acid bicycle. With each turn of the cycle one molecule of
acetyl-CoA
is consumed for every molecule of
oxaloacetate
present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of
acetyl-CoA
that produces CO2
and h2o, with the free energy thus released captured in the form of ATP.[38]
The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH2, which is similar to the oxidation of succinate to fumarate. Following, trans-Enoyl-CoA is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process equally the oxidation of malate to oxaloacetate.[39]

In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial
oxaloacetate
is an early step in the gluconeogenic pathway which converts lactate and de-aminated alanine into glucose,[37]
[38]
under the influence of high levels of glucagon and/or epinephrine in the claret.[38]
Here the add-on of
oxaloacetate
to the mitochondrion does not have a net anaplerotic effect, every bit another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to exist converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the opposite of glycolysis.[38]

In protein catabolism, proteins are broken downward by proteases into their constituent amino acids. Their carbon skeletons (i.eastward. the de-aminated amino acids) may either enter the citric acid cycle every bit intermediates (due east.1000.
alpha-ketoglutarate
derived from glutamate or glutamine), having an anaplerotic effect on the cycle, or, in the instance of leucine, isoleucine, lysine, phenylalanine, tryptophan, and tyrosine, they are converted into
acetyl-CoA
which can be burned to CO2
and water, or used to form ketone bodies, which too can just exist burned in tissues other than the liver where they are formed, or excreted via the urine or breath.[38]
These latter amino acids are therefore termed “ketogenic” amino acids, whereas those that enter the citric acrid cycle as intermediates tin can simply be cataplerotically removed by inbound the gluconeogenic pathway via
malate
which is transported out of the mitochondrion to exist converted into cytosolic oxaloacetate and ultimately into glucose. These are the so-called “glucogenic” amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acrid wheel as
oxaloacetate
(an anaplerotic reaction) or every bit
acetyl-CoA
to be disposed of equally CO2
and water.[38]

In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-iii-phosphate by way of gluconeogenesis. In many tissues, especially heart and skeletal muscle tissue, fat acids are broken down through a procedure known as beta oxidation, which results in the production of mitochondrial
acetyl-CoA, which can exist used in the citric acid bike. Beta oxidation of fatty acids with an odd number of methylene bridges produces propionyl-CoA, which is then converted into
succinyl-CoA
and fed into the citric acid wheel every bit an anaplerotic intermediate.[40]

The total energy gained from the consummate breakup of one (half-dozen-carbon) molecule of glucose by glycolysis, the formation of 2
acetyl-CoA
molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The number of ATP molecules derived from the beta oxidation of a six carbon segment of a fatty acrid concatenation, and the subsequent oxidation of the resulting three molecules of
acetyl-CoA
is xl.[
citation needed
]

Citric acid cycle intermediates serve every bit substrates for biosynthetic processes

[edit]

In this subheading, equally in the previous one, the TCA intermediates are identified by
italics.

Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which volition take significant cataplerotic effects on the cycle.[38]
Acetyl-CoA
cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA,
citrate
is removed from the citric acid cycle and carried beyond 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 every bit
malate
(and and so converted dorsum into
oxaloacetate
to transfer more
acetyl-CoA
out of the mitochondrion).[41]
The cytosolic acetyl-CoA is used for fatty acid synthesis and the production of cholesterol. Cholesterol can, in plough, exist used to synthesize the steroid hormones, bile salts, and vitamin D.[37]
[38]

The carbon skeletons of many non-essential amino acids are made from citric acid cycle intermediates. To plow them into amino acids the blastoff keto-acids formed from the citric acid bike intermediates have to larn 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 tin can provide the carbon skeletons for amino acid synthesis are
oxaloacetate
which forms aspartate and asparagine; and
blastoff-ketoglutarate
which forms glutamine, proline, and arginine.[37]
[38]

Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to grade the purines that are used equally the bases in Deoxyribonucleic acid and RNA, also every bit in ATP, AMP, GTP, NAD, FAD and CoA.[38]

The pyrimidines are partly assembled from aspartate (derived from
oxaloacetate). The pyrimidines, thymine, cytosine and uracil, class the complementary bases to the purine bases in Dna and RNA, and are also components of CTP, UMP, UDP and UTP.[38]

The bulk of the carbon atoms in the porphyrins come from the citric acid cycle intermediate,
succinyl-CoA. These molecules are an of import component of the hemoproteins, such as hemoglobin, myoglobin and various cytochromes.[38]

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 well-nigh all the gluconeogenic precursors (such as the glucogenic amino acids and lactate) into glucose by the liver and kidney.[37]
[38]

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Because the citric acrid cycle is involved in both catabolic and anabolic processes, it is known as an amphibolic pathway.

Evan Yard.W.Duo
Click on genes, proteins and metabolites below to link to respective articles.
[§ 1]

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TCACycle_WP78

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TCACycle_WP78

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|alt=TCACycle_WP78 edit]]


  1. ^

    The interactive pathway map can exist edited at WikiPathways:
    “TCACycle_WP78”.

Glucose feeds the TCA wheel via circulating lactate

[edit]

The metabolic part of lactate is well recognized as a fuel for tissues and tumors. In the classical Cori cycle, muscles produce lactate which is so taken up by the liver for gluconeogenesis. New studies suggest that lactate can exist used equally a source of carbon for the TCA bicycle.[42]

Evolution

[edit]

It is believed that components of the citric acid wheel were derived from anaerobic bacteria, and that the TCA cycle itself may take evolved more than once.[43]
Theoretically, several alternatives to the TCA cycle exist; however, the TCA wheel appears to be the nigh efficient. If several TCA alternatives had evolved independently, they all announced to take converged to the TCA cycle.[44]
[45]

See also

[edit]

  • Calvin cycle
  • Glyoxylate cycle
  • Reverse (reductive) Krebs wheel
  • Krebs cycle (unproblematic English language) [1]

References

[edit]


  1. ^


    Lowenstein, J. Chiliad. (1969).
    Methods in Enzymology, Volume 13: Citric Acid Cycle. Boston: Academic Printing. ISBN978-0-12-181870-8.



  2. ^


    Kay J, Weitzman PD (1987).
    Krebs’ citric acrid cycle: one-half a century and still turning. London: Biochemical Society. pp. 25. ISBN978-0-904498-22-vi.



  3. ^


    Wagner, Andreas (2014).
    Arrival of the Fittest
    (first ed.). PenguinYork. p. 100. ISBN9781591846468.



  4. ^


    Lane, Nick (2009).

    Life Ascending: The Ten Great Inventions of Evolution
    . New York: Westward. Westward. Norton & Co. ISBN978-0-393-06596-1.



  5. ^


    Chinopoulos C (Baronial 2013). “Which way does the citric acid cycle turn during hypoxia? The critical function of α-ketoglutarate dehydrogenase complex”
    (PDF).
    Periodical of Neuroscience Research.
    91
    (8): 1030–43. doi:10.1002/jnr.23196. PMID 23378250.


  6. ^


    a




    b




    c




    Voet D, Voet JG (2004).
    Biochemistry
    (tertiary ed.). New York: John Wiley & Sons, Inc. p. 615.



  7. ^


    Lieberman, Michael (2013).
    Marks’ basic medical biochemistry : a clinical arroyo. Marks, Allan D., Peet, Alisa. (Quaternary ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN9781608315727. OCLC 769803483.



  8. ^


    “The Nobel Prize in Physiology or Medicine 1937”. The Nobel Foundation. Retrieved
    2011-10-26
    .



  9. ^

    Chandramana, Sudeep. (2014). Inclusive Growth And Youth Empowerment: A Evolution Model For Aspirational India. Journal of Scientific discipline, Engineering science and Management. 7. 52–62.

  10. ^


    Krebs HA, Johnson WA (Apr 1937). “Metabolism of ketonic acids in animal tissues”.
    The Biochemical Journal.
    31
    (iv): 645–60. doi:x.1042/bj0310645. PMC1266984. PMID 16746382.



  11. ^


    “The Nobel Prize in Physiology or Medicine 1953”. The Nobel Foundation. Retrieved
    2011-10-26
    .



  12. ^


    Wolfe RR, Jahoor F (February 1990). “Recovery of labeled CO2 during the infusion of C-one- vs C-2-labeled acetate: implications for tracer studies of substrate oxidation”.
    The American Periodical of Clinical Nutrition.
    51
    (2): 248–52. doi:10.1093/ajcn/51.2.248. PMID 2106256.



  13. ^


    Berg JM, Tymoczko JL, Stryer L (2002). “The Citric Acid Cycle”.
    Biochemistry
    (5th ed.). Due west H Freeman. ISBN0-7167-3051-0.


  14. ^


    a




    b




    Jones RC, Buchanan BB, Gruissem Westward (2000).
    Biochemistry & molecular biology of plants
    (1st ed.). Rockville, Doctor: American Guild of Constitute Physiologists. ISBN978-0-943088-39-half-dozen.


  15. ^


    a




    b




    c




    d




    Stryer L, Berg J, Tymoczko JL (2002).
    Biochemistry. San Francisco: W. H. Freeman. ISBN978-0-7167-4684-3.



  16. ^


    Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth Exercise (October 1998). “Genetic testify for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes”.
    The Journal of Biological Chemistry.
    273
    (42): 27580–half-dozen. doi:10.1074/jbc.273.42.27580. PMID 9765291.



  17. ^


    Barnes SJ, Weitzman PD (June 1986). “Organisation of citric acid wheel enzymes into a multienzyme cluster”.
    FEBS Letters.
    201
    (2): 267–70. doi:10.1016/0014-5793(86)80621-iv. PMID 3086126. S2CID 43052163.



  18. ^


    “The citric acid cycle”.
    Khan Academy
    . Retrieved
    ten August
    2021
    .


  19. ^


    a




    b




    Porter RK, Brand Md (September 1995). “Mitochondrial proton conductance and H+/O ratio are independent of electron transport rate in isolated hepatocytes”.
    The Biochemical Periodical.
    310
    (ii): 379–82. doi:ten.1042/bj3100379. PMC1135905. PMID 7654171.



  20. ^


    Stryer L, Berg JM, Tymoczko JL (2002). “Department 18.6: The Regulation of Cellular Respiration Is Governed Primarily by the Need for ATP”.
    Biochemistry. San Francisco: Due west. H. Freeman. ISBN978-0-7167-4684-3.



  21. ^


    Rich PR (December 2003). “The molecular mechanism of Keilin’s respiratory chain”.
    Biochemical Society Transactions.
    31
    (Pt 6): 1095–105. doi:10.1042/BST0311095. PMID 14641005. S2CID 32361233.



  22. ^


    “Citric acrid cycle variants at MetaCyc”.


  23. ^


    Sahara T, Takada Y, Takeuchi Y, Yamaoka Northward, Fukunaga N (March 2002). “Cloning, sequencing, and expression of a gene encoding the monomeric isocitrate dehydrogenase of the nitrogen-fixing bacterium, Azotobacter vinelandii”.
    Bioscience, Biotechnology, and Biochemistry.
    66
    (3): 489–500. doi:10.1271/bbb.66.489. PMID 12005040. S2CID 12950388.



  24. ^


    van der Rest ME, Frank C, Molenaar D (December 2000). “Functions of the membrane-associated and cytoplasmic malate dehydrogenases in the citric acid cycle of Escherichia coli”.
    Journal of Bacteriology.
    182
    (24): 6892–nine. doi:x.1128/jb.182.24.6892-6899.2000. PMC94812. PMID 11092847.



  25. ^


    Lambeth DO, Tews KN, Adkins S, Frohlich D, Milavetz BI (August 2004). “Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues”.
    The Periodical of Biological Chemistry.
    279
    (35): 36621–4. doi:x.1074/jbc.M406884200. PMID 15234968.



  26. ^


    Mullins EA, Francois JA, Kappock TJ (July 2008). “A specialized citric acid cycle requiring succinyl-coenzyme A (CoA):acetate CoA-transferase (AarC) confers acetic acid resistance on the acidophile Acetobacter aceti”.
    Journal of Bacteriology.
    190
    (14): 4933–twoscore. doi:10.1128/JB.00405-08. PMC2447011. PMID 18502856.



  27. ^


    Corthésy-Theulaz IE, Bergonzelli GE, Henry H, Bachmann D, Schorderet DF, Blum AL, Ornston LN (October 1997). “Cloning and characterization of Helicobacter pylori succinyl CoA:acetoacetate CoA-transferase, a novel prokaryotic member of the CoA-transferase family”.
    The Journal of Biological Chemistry.
    272
    (41): 25659–67. doi:ten.1074/jbc.272.41.25659. PMID 9325289.



  28. ^


    Baughn Advertisement, Garforth SJ, Vilchèze C, Jacobs WR (Nov 2009). “An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acrid cycle of Mycobacterium tuberculosis”.
    PLOS Pathogens.
    5
    (11): e1000662. doi:10.1371/journal.ppat.1000662. PMC2773412. PMID 19936047.



  29. ^


    Zhang S, Bryant DA (December 2011). “The tricarboxylic acid cycle in cyanobacteria”.
    Science.
    334
    (6062): 1551–three. Bibcode:2011Sci…334.1551Z. doi:10.1126/scientific discipline.1210858. PMID 22174252. S2CID 206536295.



  30. ^


    Dang 50, Su SM (June 2017). “Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Evolution”.
    Annual Review of Biochemistry.
    86
    (1): 305–331. doi:10.1146/annurev-biochem-061516-044732. PMID 28375741.



  31. ^


    Yong C, Stewart GD, Frezza C (March 2020). “Oncometabolites in renal cancer”.
    Nature Reviews. Nephrology.
    sixteen
    (three): 156–172. doi:10.1038/s41581-019-0210-z. PMC7030949. PMID 31636445.



  32. ^


    Gelman SJ, Mahieu NG, Cho K, Llufrio EM, Wencewicz TA, Patti GJ (December 2015). “Evidence that 2-hydroxyglutarate is non readily metabolized in colorectal carcinoma cells”.
    Cancer & Metabolism.
    3
    (1): xiii. doi:ten.1186/s40170-015-0139-z. PMC4665876. PMID 26629338.



  33. ^


    Rotili D, Mai A (June 2011). “Targeting Histone Demethylases: A New Avenue for the Fight confronting Cancer”.
    Genes & Cancer.
    2
    (half-dozen): 663–79. doi:10.1177/1947601911417976. PMC3174264. PMID 21941621.



  34. ^


    Ivannikov MV, Macleod GT (June 2013). “Mitochondrial free Ca²⁺ levels and their furnishings on energy metabolism in Drosophila motor nervus terminals”.
    Biophysical Journal.
    104
    (11): 2353–61. Bibcode:2013BpJ…104.2353I. doi:10.1016/j.bpj.2013.03.064. PMC3672877. PMID 23746507.



  35. ^


    Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, et al. (October 1975). “Regulation of mammalian pyruvate dehydrogenase”.
    Molecular and Cellular Biochemistry.
    9
    (1): 27–53. doi:10.1007/BF01731731. PMID 171557. S2CID 27367543.



  36. ^


    Koivunen P, Hirsilä M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (February 2007). “Inhibition of hypoxia-inducible gene (HIF) hydroxylases past citric acrid cycle intermediates: possible links between cell metabolism and stabilization of HIF”.
    The Journal of Biological Chemistry.
    282
    (seven): 4524–32. doi:ten.1074/jbc.M610415200. PMID 17182618.


  37. ^


    a




    b




    c




    d




    e




    Voet, Donald; Judith G. Voet; Charlotte West. Pratt (2006).
    Fundamentals of Biochemistry, 2nd Edition. John Wiley and Sons, Inc. pp. 547, 556. ISBN978-0-471-21495-iii.


  38. ^


    a




    b




    c




    d




    eastward




    f




    g




    h




    i




    j




    g




    l




    m




    n




    o




    Stryer, Lubert (1995). “Citric acrid cycle”.
    In: Biochemistry
    (4th ed.). New York: W. H. Freeman and Company. pp. 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773. ISBN978-0-7167-2009-vi.



  39. ^


    Garrett, Reginald H.; Grisham, Charles Grand. (2013).
    Biochemistry
    (5th ed.). Belmont, CA: Brooks/Cole, Cengage Learning. pp. 623–625, 771–773. ISBN9781133106296. OCLC 777722371.



  40. ^


    Halarnkar PP, Blomquist GJ (1989). “Comparative aspects of propionate metabolism”.
    Comparative Biochemistry and Physiology. B, Comparative Biochemistry.
    92
    (2): 227–31. doi:10.1016/0305-0491(89)90270-8. PMID 2647392.



  41. ^


    Ferré P, Foufelle F (2007). “SREBP-1c transcription factor and lipid homeostasis: clinical perspective”.
    Hormone Research.
    68
    (2): 72–82. doi:x.1159/000100426. PMID 17344645.
    this procedure is outlined graphically in folio 73



  42. ^


    Hui Southward, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. (November 2017). “Glucose feeds the TCA cycle via circulating lactate”.
    Nature.
    551
    (7678): 115–118. Bibcode:2017Natur.551..115H. doi:ten.1038/nature24057. PMC5898814. PMID 29045397.



  43. ^


    Gest H (1987). “Evolutionary roots of the citric acid cycle in prokaryotes”.
    Biochemical Society Symposium.
    54: 3–16. PMID 3332996.



  44. ^


    Meléndez-Hevia Due east, Waddell TG, Cascante Thou (September 1996). “The puzzle of the Krebs citric acid bike: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution”
    (PDF).
    Journal of Molecular Evolution.
    43
    (3): 293–303. Bibcode:1996JMolE..43..293M. doi:10.1007/BF02338838. PMID 8703096. S2CID 19107073.



  45. ^


    Ebenhöh O, Heinrich R (Jan 2001). “Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems”
    (PDF).
    Message of Mathematical Biology.
    63
    (1): 21–55. doi:10.1006/bulm.2000.0197. PMID 11146883. S2CID 44260374.


External links

[edit]

  • An animation of the citric acid cycle at Smith College
  • Citric acid cycle variants at MetaCyc
  • Pathways continued to the citric acid cycle at Kyoto Encyclopedia of Genes and Genomes
  • metpath: Interactive representation of the citric acrid wheel



During the Citric Acid Cycle What Happens to Acetyl Coa

Source: https://en.wikipedia.org/wiki/Citric_acid_cycle