An inner mitochondrial membrane CPT2 then converts the long-chain acylcarnitine back to long-chain acyl-CoA. An overview of fatty acid oxidation is provided in Figure 1.
Fatty acids primarily enter a cell via fatty acid protein transporters on the cell surface. CPT1 then converts the long-chain acyl-CoA to long-chain acylcarnitine. The fatty acid moiety is transported by CAT across the inner mitochondrial membrane.
CPT2 then converts the long-chain acylcarnitine back to long-chain acyl-CoA. There has been considerable effort in recent years to elucidate the mechanisms by which the fatty acids are taken up by cells, particularly determining whether fatty acids are transported across the cellular membrane by simple diffusion or whether this transport is facilitated by membrane-associated proteins.
While various results support both methods of transport, transport by membrane-associated proteins is believed to be the predominant means of fatty acid uptake into cells [2]. Various membrane proteins that facilitate cellular fatty acid uptake have been identified.
Stremmel et al. This result suggested that a significant portion of fatty acid uptake is dependent on protein-mediated transport in different kinds of cells [3]. The expression of this 63 kDa integral membrane protein in a stable fibroblast cell line resulted in a fold increase in long-chain fatty acid transport. FATP1 is predominantly expressed in heart and skeletal muscles [5]. FATP4 is essential for absorption of dietary lipids and has a critical role in normal skin structure and function.
A fatty acid must be converted to fatty acyl-CoA in order for it to enter the mitochondria and be oxidized [1]. ACC catalyzes the carboxylation of acetyl-CoA producing malonyl-CoA, which can be used by fatty acid synthase for fatty acid biosynthesis [1].
While malonyl-CoA is used as a substrate for fatty acid biosynthesis, malonyl-CoA is also a potent inhibitor of mitochondrial fatty acid uptake secondary to inhibition of CPT1 Figure 2 [1]. There are two forms of ACC, a kDa ACC1 isoform, which is highly expressed in the liver and adipose tissue, and a kDa ACC2 isoform which is more specific to highly metabolic organs such as skeletal muscle and the heart [1]. Next, enoyl-CoA hydratase removes the double bond just formed, in the process of adding a hydroxyl group to the third carbon down from the CoA group and a hydrogen on the second carbon down from the CoA group.
Hydroxyacyl-CoA dehydrogenase removes the hydrogen in the hydroxyl group just attached and in the process produces a NADH. In the final step, ketoacyl-CoA thiolase attaches a CoA group on to the third carbon down from the CoA group resulting in the formation of two molecules, an acetyl-CoA and an acyl-CoA that is two carbons shorter. Long-term regulation of ACC depends on regulation of its gene expression.
For example, Adam et al. Generally, the level of malonyl-CoA is decreased when MCD activity is increased, resulting in an elevated rate of fatty acid oxidation. However, MCD appears to be primarily regulated by transcriptional means discussed later. Mitochondrial carnitine palmitoyl transferase CPT :. The CPT isoform, CPT1, resides on the inner surface of the outer mitochondrial membrane and is a major site of regulation of mitochondrial fatty acid uptake [1].
On the early Earth, the global ocean was more acidic, however, on the order of pH 6, because vast amounts of CO 2 dissolved in it. The polarity of the gradient is the same as that in modern cells: more alkaline on the inside than on the outside, generating a proton motive force from outside to in Martin and Russell , Lane et al.
Such a geochemically generated ion gradient could have been harnessed by an ATPase at the origin of biochemistry, once genes and proteins had evolved Martin and Russell, ; Martin, This solves the problem of how ion gradients arose before there were specific biochemical mechanisms to generate them: the first biochemical systems arose in environments where geochemical ion gradients were naturally existing Russell and Hall, ; Martin and Russell, ; Lane et al.
Again, the polarity of ion gradients at alkaline hydrothermal vents more alkaline on the inside than on the outside is exactly the same as in cells Martin and Russell, ; Lane and Martin, The evolutionary relationship of substrate-level phosphorylation SLP to chemiosmotic coupling is traditionally viewed as SLP coming first with chemiosmotic coupling coming later Lipmann, ; Decker et al.
Although serpentinizing systems solve several problems in early physiological evolution, they present another: How, in terms of energetics, could genes and proteins protein synthesis is ATP and GTP dependent have evolved before a universal mechanism of ATP synthesis, ion gradient harnessing via a rotor—stator ATP synthase, which is a protein encoded by genes, had come to be?
This question touches many facets of the origins problem, because it concerns the relationship between nucleic acids as molecular memory, peptides as catalysts, and the coupling of environmental energy to the polymerization reactions that generate both classes of biopolymers from their monomers.
As with most debates, the debate is older, as summarized yet again by Lipmann ; his opening statement on p. All efforts seem to be fixed exclusively on using presumably available energy sources, for example, electric discharges, for synthesizing nucleotides and amino acids and, therefrom, polynucleotides and polypeptides from various carbon—nitrogen sources.
As I interpret it, the fascination with the two classes of compounds indicates the assumption that they are essential at the very outset. Being dissatisfied with this fixation on starting with the hen rather than with the egg, I have attempted to find alternatives. I am afraid that what I have to say will be just as much natural philosophy as necessarily most discussion on the origin of life need be at present.
But try we must. Nonetheless, a common criticism of hydrothermal systems as sites for biochemical origins is that they are full of water. This criticism typically comes from the genetics first camp and is based on the argument that, in aqueous solution, peptide bonds and the phosphoester bonds linking nucleotides will hydrolyze, leading to an inference that systems containing genetic material could not have evolved in a permanently aqueous environment Bada and Lazcano, ; Orgel, Rather than prompt a conclusion that life must have evolved where there was no water Benner and Kim, , the thought about polymer hydrolysis should prompt the question: How does life deal with this problem?
The answer is that life harnesses environmentally available energy and couples it to the synthesis of peptides and nucleic acids such that their polymerization is much faster than their hydrolysis. Let us assume for the sake of argument that it has always been this way. The hen to which Lipmann alluded was biopolymers; the egg was energy harnessing.
In biological systems, energy is mainly saved and spent in the currency of high-energy phosphate bonds: acyl phosphates, phosphoanhydrides, phosphoamides, carbamoyl phosphate, and phosphoenolate, all of which were known in Lipmann, Phosphorus forms long covalent bonds with oxygen Wald, This invites nucleophilic attack by water.
The P—O and P—N bonds in the organophosphates of energy metabolism have high free energies of hydrolysis. This release of free energy, if coupled to a slightly endergonic reaction, can make the reaction go forward.
Coupled to many reactions, the hydrolysis of high-energy bonds makes the metabolism of a whole cell life go forward. That means that the high-energy bonds must constantly be resynthesized; otherwise, life comes to a halt. An Escherichia coli cell synthesizes roughly of 30 billion ATP 30 pg or approximately 30 times its bodyweight 1 pg per cell division Akashi and Gojobori, , a human synthesizes about a bodyweight of ATP per day.
As Lipmann pointed out, there are two mechanisms to make ATP. There is substrate-level phosphorylation Lipmann called it fermentative phosphorylation or extract phosphorylation in which a phosphate-containing carbon compound Table 1 with a sufficiently high-energy bond phosphorylates ADP in a stoichiometric reaction. The other way to make ATP is the chemiosmotic mechanism of Mitchell with ion pumping plus ion gradient harnessing, which Lipmann called oxidation-chain phosphorylation because the mechanism of electron transfer to coupling via the ATP synthase had not yet been worked out.
Lipmann concluded that substrate-level phosphorylation entailed a far simpler machinery; hence, it was the more ancient form of making high-energy phosphate bonds.
But Lipmann blazed a too seldom questioned trail in origins literature by suggesting that the participation of high-energy phosphate bonds in metabolism started with inorganic pyrophosphate PP i as the first chemical energy currency, coupled with his notion that SLP is more ancient than the ion gradient phosphorylation, which led to the idea that the entry of high-energy phosphate bonds into primitive metabolism came from high-energy phosphate bonds in phosphorus minerals in the environment.
It furthermore distracts from the main issue at hand—the coupling of exergonic reactions of carbon reduction to early energy conservation see following section.
That is not to say that there are no PP i -dependent reactions in metabolism—there are many. The point is that no biological systems are known to this author that access environmental PP i or environmental polyphosphates as a source of energy. Stated another way, what cell will grow chemotrophically from PP i or polyphosphate without the involvement of redox chemistry? None is probably the answer. The only examples from biology in which environmentally available phosphorous compounds play a role in energy metabolism involve phosphite as an electron donor in ion-pumping electron transport chains Schink and Friedrich, The phosphite oxidizers are fascinating and important; they also clearly show that there is enough phosphite in the environment to support the existence of phosphite-reducing electron transport chains.
Another problem with PP i that is equally pressing, if not more so, is that PP i has a lower free energy of hydrolysis than glucosephosphate Table 1 ; it has low group transfer potential and is thus fighting a steeply uphill energetic battle in any effort to phosphorylate ADP for SLP or to activate any metabolic compound via formation of phosphoanhydride, phosphoester, or similar bonds.
When de Duve suggested that phosphorolysis of a thioester bond to form an acyl phosphate, as it occurs in the reaction mechanism of glyceraldehydephosphate dehydrogenase Figure 4A , might mark the entry of phosphate into metabolism, he might have had the right kind of reaction mechanism, although it appears, from my perspective, that he put it in the context of the wrong upstream and downstream reactions.
Leaning on the GAPDH reaction Figure 4A , de Duve was suggesting that the oxidation of reduced carbon compounds present in the environment provided the source of energy.
That is exactly what Wald had said 27 years prior about the origin of metabolism: life started from glucose fermentations see Table 1 of Wald, Whatever happened to Mereschkowsky and autotrophic origins? The idea that there were enough free sugars lying around in the environment to provide an energy source for first life is still current in modern literature Keller et al.
The oxidation of preexisting reduced carbon compounds as a source of energy is couched in the outdated Maden, concept of an organic soup, year-old notion tracing to Oparin and Haldane concerning the origin of organic compounds in the first place.
Soup was once popular Garrison et al. That is, de Duve was deriving thioesters via analogy to heterotrophic metabolism. Figure 4. Energy conservation as high-energy phosphate bonds from carbon oxidation and carbon reduction [modified from Martin and Cerff ]. A Mechanism of the D -glyceraldehydephosphate dehydrogenase reaction in the glycolytic oxidative direction to generate the mixed anhydride bond in 1,3-bisphospho- D -glycerate. The vertical arrow underscores the oxidative nature of the reaction in the energy-conserving direction.
Modified from Martin and Cerff and Martin and Thauer The reactions are drawn from data compiled in Svetlitchnaia et al. Some methanogens can generate reduced ferredoxin via an energy-conserving hydrogenase, Ech, which does not entail bifurcation, but operates at the expense of an ion gradient, the generation of which demands bifurcation at the Mvh—Hdr complex Thauer et al. In heterotrophic metabolism, SLP is always coupled to oxidation of reduced carbon substrates Decker et al.
In autotrophy, carbon backbones unfold in a very natural and orderly manner that specifically generates the compounds of the acetyl CoA pathway Figure 3. Here, a point cannot be overemphasized. In SLP, the high-energy organophosphate bonds that are used to make ATP are formed by reactions of reactive carbon backbones with phosphate.
It is not the reaction of reactive phosphorus compounds with unreactive organic substrates. It is the reaction of unreactive phosphate with reactive carbon compounds.
The energy in the high-energy organophosphate bonds that are used for SLP acyl phosphates, phosphoenolate resides in carbon, not in phosphorus.
In autotrophic metabolism, acetyl phosphate can be synthesized for SLP during the process of CO 2 reduction. In metabolism, phosphate is a cofactor, not a source of energy. It is an innocent bystander that forms a high-energy bond by its ability to perform nucleophilic attack of a reactive carbonyl.
Does Figure 4B recapitulate a primordial reaction sequence coupling of CO 2 reduction and energy metabolism? It well could be. Does that energy coupling work without enzymes? So far, no synthesis of acyl phosphates from CO 2 and P i has been reported.
Would acyl phosphates from scratch be a big advance? It would help to explain how early energetic coupling was possible. Findings from various disciplines tend to home in on the acetyl CoA pathway when it comes to origins. Investigations into ancient metabolism from the standpoint of modern metabolic networks are uncovering clues that converge on the acetyl CoA pathway Goldford et al. Autocatalytic cycles can be identified within the metabolism of methanogens and acetogens Xavier et al. Reactive chemical networks based on thioesters have been reported Semenov et al.
Starting from products of the acetyl CoA pathway, reactions of the reverse citric acid cycle take place in the absence of enzymes Muchowska et al.
Genomic reconstructions of LUCA indicate that it lived from gasses, using reactions and enzymes germane to the acetyl CoA pathway Weiss et al.
The enzymes of the acetyl CoA pathway are not only replete with transition metal sulfide centers Russell and Martin, , but they also contain half of all the carbon—metal bonds currently known in biology Martin, Carbon—metal bonds are extremely rare in metabolism, and they are ancient. They occur only in enzymes that form the interface between metabolism and the gasses from which LUCA lived H 2 , CO 2 , N 2 , or in enzymes and cofactors that transfer methyl groups, as shown in Figure 4B , or in cofactors that initiate radical reactions Martin, They appear, to me at least, to be relicts of the catalysts that gave rise to primordial physiology.
And what good are acyl phosphates? They are energy currency, better than ATP. A look at Katchalsky and Paecht , p. Clearly, an energetic coupling of CO 2 reduction to acyl or amino acyl phosphate synthesis would enable a great many biologically relevant reactions, such as peptide synthesis. One thinks of small molecule chemical networks of the kind that Kauffman had in mind Xavier et al. Although a number of possible systems of this type have been discussed, no experimental demonstration has been made.
Spontaneous reactions that couple a biological driver reaction to synthesis of a biological energy currency cannot be far away. The overall reaction will probably look very much like acetogen energy metabolism, but with metals in place of enzymes.
If carbon-based energy metabolism came first, carbon metabolism and, given a natural source of activated nitrogen Preiner et al. Prior to the publication of this article, a reader lamented that I seemed to be assuming retrograde evolution of pathways without saying so. This article is not about retrograde evolution of pathways; it is about the antiquity of a CO 2 fixing pathway in the context autotrophic origins, which posit the outward evolution of pathways emanating from CO 2 , which is the opposite of retrograde evolution.
Other readers might encounter the same problem, so it is worthwhile to briefly recapitulate retrograde pathway evolution and contrast it to the ideas in the present article. The concept of retrograde evolution of pathways traces to an article by Horowitz , who argued that in the beginning there was a rich organic soup of the components from which cells are composed, amino acids bases and the like, in line with ideas of Oparin.
These components, the products of modern pathways, became depleted through biological activity, creating pressure to synthesize them from their immediate biosynthetic precursors, which are presumed to exist in the soup as well. Notably, Horowitz assumes the existence of heterotrophic cells as the starting point of retrograde pathway evolution. Depletion of a given product Z creates pressure for the terminal enzyme in the pathway to be fixed so as to supply Z from precursor Y in a one-step pathway.
In this way, pathways and metabolism as a whole evolved from the distal tips, the products, inward to the proximal core of central intermediates from which all products amino acids and bases are synthesized. From tips to root means backward steps in evolution along the pathway relative to the biosynthetic direction, hence retrograde, although Horowitz did not use that word. Horowitz required the pathway evolving species to be heterotrophic for the compound in question, or in modern terms auxotrophic for all pathway products, taken across all pathways.
A related concept is that of Ycas , who suggested that gene duplications for an initially small number of enzymes of relaxed substrate specificity gave rise to toward a larger collection of enzymes each having higher substrate specificity. The theories of Horowitz and Ycas concern the vector of gene and enzyme evolution after the origin of organisms. The retrograde model of Horowitz explicitly posits that the first organisms were heterotrophs.
Autotrophic theories assume that the first organisms were autotrophs that obtained carbon from CO 2. They differ from heterotrophic theories in that they assume that the organic molecules from which life arose were synthesized from CO 2 and that the evolution of biochemical pathways to complex organics amino acids and bases thus recapitulates a vector of biochemical evolution that starts from CO 2 and moves outward toward the tips, or products, of metabolism.
In other words, heterotrophic origin theories operate via consumption of preformed products, whereas autotrophic origin theories operate via synthesis of products from CO 2. In contrast to Horowitz , autotrophic theories do not start with organisms. In contrast to Ycas , they do not start with genes. Rather autotrophic theories entail the concept of chemical or physiological evolution before genes, starting from CO 2.
Investigations of metabolic maps to uncover ancient cores and structures in metabolism are much in line with that view, as they uncover conservation surrounding an autotrophic core Goldford et al. That said, what do autotrophic theories say about the evolution of genetically encoded biochemical pathways? Genes require the existence of the code; this article is not about the origin of the code.
Once genes had arisen we all have to agree that they did arise somewhere at some point , it is eminently reasonable to posit that the first genes to arise and evolve, in general, were those that anchored the genetic code in place, namely, aminoacyl tRNA synthetases Carter and Wills, In terms of physiology, the first genes to arise and evolve were likely those that channeled a necessarily exergonic preexisting flux of carbon and nitrogen into components that reinforced the synthesis of genes and proteins Martin and Russell, A survey of genes that trace to LUCA found precisely, namely, eight genes for aminoacyl tRNA synthetases and several enzymes involved in the acetyl CoA pathway, in nitrogen metabolism, in H 2 assimilation, in cofactor biosynthesis, and in the synthesis of amino acids, bases, and modified bases Weiss et al.
Of the autotrophic pathways known, only the acetyl CoA pathway occurs in both bacteria and archaea and enables ATP synthesis during CO 2 fixation Berg et al. The interested reader is directed to Table S10 of Mall et al.
In line with its favorable thermodynamics, the acetyl CoA pathway is also the only one of the autotrophic pathways known that has been shown so far to operate in toto without enzymes, as acetate and pyruvate are generated from H 2 and CO 2 by mineral catalysts alone Preiner et al.
Thus, from the standpoint of thermodynamics, it is the one from which to start Figure 3. That would provide formate, acetate, and pyruvate, which in acetogens and methanogens spill over into the incomplete reverse citric acid cycle as the main source of carbon skeletons for biosynthesis Martin and Russell, ; Fuchs, ; Goldford et al.
The central proposition of autotrophic origins is that first biochemical pathways evolved outward from such a central core in a way that brought forth central intermediary metabolism from inorganically catalyzed non-enzymatic reactions.
Inorganically catalyzed reactions came to be accelerated and channeled into metabolism-like conversions by accrual of organic catalysts organic cofactors or their abiotic precursors and then finally enzymes.
In that sequence of events, the cofactors themselves could have been products of inorganic catalysis, with enzymes, however, being the products of genes. This sequence of pathway evolution, namely, a sequence of CO 2 assimilating reactions starting from inorganic catalysts, progressing to organic catalysts cofactors , and on to enzymatic gene encoded catalysts, entails the very broad premise that the reactions of central metabolism leading to products amino acids and bases tend to take place naturally.
Catalysts merely accelerate chemical reactions that tend to take place anyway, or the catalysts can alter the immediate products in the case kinetically controlled reactions.
In that sense, the evolution of pathways under such a set of premises for autotrophic origins is prepatterned Ger. Some readers will ask why not use the word palimpsestic instead of patterned. Palimpsestic, in addition to lacking all prosody, emphasizes the process of overbuilding or overwriting a prior state. Patterned, and more specifically vorgezeichnet , places the emphasis on the process of putting the original pattern, the ancestral state, in place. Patterned evolution of pathways emphasizes the process of generating the original pattern, namely, the natural reactions of organic compounds.
Thus, the concept of patterned evolution of pathways is the autotrophic counterpart of retrograde pathway evolution inherent to heterotrophic theories.
Patterned pathway evolution has it that the reactions that comprise biochemical pathways were etched into the space of all possible chemical reactions according to kinetic and thermodynamic constraints, with environmentally available and novel synthesized catalysts bearing upon the relative rates of competing reactions. As pathways evolved forward, the spontaneous chemical reactions of preceding products determined the vector of evolutionary progression.
The connections between products of different pathways, sometimes connecting pathway intermediates to generate new routes and products widespread in cofactor biosynthesis as one moves distal to the core, emerge as a natural result of patterned pathway evolution, as does the noteworthy thermodynamic stability of the main pathway end products, amino acids, and bases.
Patterned evolution of pathways would readily explain why so many reactions in metabolism work well without enzymes Martin and Russell, ; Keller et al. The same reader who was interested in retrograde evolution also suggested that I discuss an alternative theory that life evolved from large amounts of abiotically formed acetate. As it stands, there is no such theory out there in the literature to discuss, nor is there currently clear evidence for accumulation of abiotic acetate in large amounts, in contrast to clear evidence for abiotic accumulation of formate Lang et al.
Furthermore, if life started from acetate, the extraction of energy would be problematic. Acetate disproportionation to H 2 and CO 2 for energy metabolism generally requires a syntrophic partner that can scavenge the H 2 so that the H 2 -producing reaction is exergonic Hattori et al. Acetate disproportionation might, however, have arisen very early after acetogenesis Martin and Russell, The alternative energy extraction route, acetate oxidation using high-potential terminal acceptors, is not an option at origins for the same reason that methane oxidation is not an option at origins: In the presence of high-potential acceptors, the reduced carbon compounds that need to accumulate for metabolism and life to arise in the first place are converted to CO 2 Sousa et al.
The synthesis of acetate from H 2 and CO 2 is exergonic all by itself, as long as there is sufficient H 2 and as long as there are no strong oxidants around. Acetate synthesis from H 2 and CO 2 is hence a good starting point for metabolic origins. Figure 5 summarizes metabolism in an ancient cell; an earlier and more preliminary version of the figure is found in Martin and Russell It conveys an approximation of the life process as a chemical reaction using the example of an acetogen.
The starting point of Figure 5 is a study by Drake and colleagues Daniel et al. For Clostridium thermoaceticum , they found that during growth on H 2 and CO 2 approximately 0. That is shown with the large gray arrow at the left of Figure 5. Thus, if we start with 2, atoms of carbon in CO 2 , approximately 2, of them are converted to acetate for energy metabolism, and approximately of them go to cell mass.
The fate of those carbons in metabolism is given by Fuchs , who provided a summary of carbon distribution in an idealized primordial metabolism based on the acetyl CoA pathway. The numbers next to the arrows in Figure 5 indicate the percent of acetyl moieties going toward C 2 metabolism or being extended by further CO 2 incorporation as given in Figure 6 of Fuchs Figure 5. Idealized primordial metabolism for a hydrogenotrophic acetogen see text. The carbon pathways are taken from Figure 6 of Fuchs ; the amino acid biosynthetic families are taken from Berg et al.
For fairness, Daniel et al. Numbers next to arrows in carbon pathways are from Fuchs and indicate the approximate percentage of flux. Relative width of carbon flux arrows is drawn roughly to scale, including the large gray arrow at left, to underscore the relative flux of material through the cell large versus the residue that remains small.
The acetyl CoA pathway roughly as indicated in Figure 4B resides within the large gray arrow and is not shown in detail. Ten amino acids contain one additional carbon beyond the C 2 starting unit, six amino acids have two additional carbons, and four amino acids have three additional carbons that are added from CO 2.
Had we started with acetyl units carbon atoms , pyruvate synthesis adds 71 more carbon atoms, oxaloacetate synthesis adds 22 more carbon atoms, and 2-oxoglutarate synthesis adds nine more Fuchs, , yielding additional carbon atoms.
Thus, per carbon atoms from acetyl CoA, approximately 50 more are incorporated after acetyl CoA synthesis. The acetyl CoA pathway provides approximately two-thirds of the carbon, roughly one-third coming from subsequent incorporations. The energy for that comes from acetogenesis, which delivers approximately 0. For the 1, acetate produced, that yields approximately ATP, which, if we consult Stouthamer regarding the rough distribution of energy costs across the cell, is enough to make approximately 52 peptide bonds.
But an average amino acid has five carbons, so that there is enough energy to make 52 peptide bonds but only enough carbon to make 18 amino acids.
The available energy for peptide synthesis exceeds the available carbon for peptide synthesis by approximately a factor of three.
Can that be right? A three-fold excess of energy relative to protein cell mass seems odd at first sight, but in Figure 5 , we have not considered maintenance energy or ATP spilling, which can be substantial.
Curr Opin Cell Biol. Author manuscript; available in PMC Apr 1. Lei Shi and Benjamin P. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Curr Opin Cell Biol. See other articles in PMC that cite the published article. Abstract Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Introduction In response to a dynamic nutrient environment, cells must assess their metabolic state to decide whether to grow, survive, or die.
Open in a separate window. Figure 1. Schematic model proposing a general logic of acetyl-CoA utilization under fed versus fasted or growth versus survival states Under fed or growth states, acetyl-CoA is directed out of the mitochondria and to the cytosol and nucleus for use in lipid synthesis or histone acetylation. Survival or Fasted State - High acetyl-CoA in mitochondria During starvation, cells must typically shift from growth to survival mode and alter metabolism towards functions important for viability.
Sensing of acetyl-CoA through protein acetylation modifications How might cells actually sense the abundance of acetyl-CoA? Figure 2. Dynamic acetylation and deacetylation of proteins A The acetylation of proteins may be catalyzed by acetyltransferase enzymes or can occur spontaneously through reaction with acetyl-CoA directly.
Stoichiometry of acetylation modifications Given the thousands of newly identified acetylated proteins, a pertinent question is what proportion of each protein is acetylated? Implications for sirtuin function The accumulation of acetyl-CoA in subcellular compartments may also necessitate the activity of deacetylase enzymes to remove non-enzymatic acetylation modifications that could intentionally or unintentionally compromise protein function [ 28 , 53 , 54 ].
Summary and perspective In summary, there is now compelling evidence that acetyl-CoA represents a fundamental gauge of cellular metabolic state that is monitored by the cell by way of distinctive protein acetylation modifications.
Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. Influence of metabolism on epigenetics and disease. Hardie DG. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis.
Canto C, Auwerx J. Endocr Rev. Coenzyme A and its derivatives: renaissance of a textbook classic. Biochem Soc Trans. Srere PA. The citrate cleavage enzyme.
Distribution and purification. J Biol Chem. The molecular physiology of citrate. ATP-citrate lyase links cellular metabolism to histone acetylation. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol Cell. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Shi L, Tu BP. Regulation of hepatic fatty acid oxidation and ketone body production.
Annu Rev Biochem. Jackowski S, Leonardi R. Deregulated coenzyme A loss of metabolic flexibility and diabetes. Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state. PLoS One. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Uyeda K, Repa JJ.
Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. The authors demonstrated nucleocytosolic acetyl-CoA repressed autophagy and ATG7 gene expression in yeast.
Regulation of autophagy by cytosolic acetyl-coenzyme A. Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. The conversion of pyruvate to acetyl CoA is a three-step process. Breakdown of Pyruvate : Each pyruvate molecule loses a carboxylic group in the form of carbon dioxide. Step 1. A carboxyl group is removed from pyruvate, releasing a molecule of carbon dioxide into the surrounding medium.
Note: carbon dioxide is one carbon attached to two oxygen atoms and is one of the major end products of cellular respiration. The result of this step is a two-carbon hydroxyethyl group bound to the enzyme pyruvate dehydrogenase; the lost carbon dioxide is the first of the six carbons from the original glucose molecule to be removed.
This step proceeds twice for every molecule of glucose metabolized remember: there are two pyruvate molecules produced at the end of glycolysis ; thus, two of the six carbons will have been removed at the end of both of these steps.
Step 2. Step 3. The enzyme-bound acetyl group is transferred to CoA, producing a molecule of acetyl CoA. This molecule of acetyl CoA is then further converted to be used in the next pathway of metabolism, the citric acid cycle. Acetyl CoA links glycolysis and pyruvate oxidation with the citric acid cycle. In the presence of oxygen, acetyl CoA delivers its acetyl group to a four-carbon molecule, oxaloacetate, to form citrate, a six-carbon molecule with three carboxyl groups.
During this first step of the citric acid cycle, the CoA enzyme, which contains a sulfhydryl group -SH , is recycled and becomes available to attach another acetyl group. The citrate will then harvest the remainder of the extractable energy from what began as a glucose molecule and continue through the citric acid cycle. In the citric acid cycle, the two carbons that were originally the acetyl group of acetyl CoA are released as carbon dioxide, one of the major products of cellular respiration, through a series of enzymatic reactions.
Acetyl CoA and the Citric Acid Cycle : For each molecule of acetyl CoA that enters the citric acid cycle, two carbon dioxide molecules are released, removing the carbons from the acetyl group.
In addition to the citric acid cycle, named for the first intermediate formed, citric acid, or citrate, when acetate joins to the oxaloacetate, the cycle is also known by two other names.
The TCA cycle is named for tricarboxylic acids TCA because citric acid or citrate and isocitrate, the first two intermediates that are formed, are tricarboxylic acids. Additionally, the cycle is known as the Krebs cycle, named after Hans Krebs, who first identified the steps in the pathway in the s in pigeon flight muscle.
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