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Biological oxidation reactions serve two functions, as described in the previous study guide. Oxidation of organic molecules can produce new molecules with different properties. For example, increases in solubility is observed on hydroxylation of aromatic substrates by cytochrome P450. Likewise, amino acids can by oxidized to produce neurotransmitters. Most biological oxidation reactions occur, however, to produce energy to drive thermodynamically unfavored biological processes such as protein and nucleic acid synthesis, or motility. Chemical potential energy is not just released in biological oxidation reactions. Rather, it is transduced into a more useful form of chemical energy in the molecule ATP (adenosine triphosphate). This guide will discuss the properties that make ATP so useful biologically, and how exergonic biological oxidation reactions are coupled to the synthesis of ATP.


ATP contains two phosphoanhydride bonds (connecting the 3 phosphates together) and one phosphoester bond (connecting a phosphate to the ribose ring). The pKa's for the reactions HATP3- ---> ATP4- + H+ and HADP2- ---> ADP3- + H+ are about 7.0, so the overall charges of ATP and ADP at physiological pH are -3.5 and -2.5, respectively. Each of the phosphorous atoms are highly electrophilic and can react with nucleophiles like the OH of water or an alcohol. As we discussed earlier, anhydrides are thermodynamically more reactive than esters which are more reactive than amides. The large negative DGo (-7.5 kcal/mol) for the hydrolysis (a nucleophilic substitution reaction) of one of the phosphoanhydride bonds can be attributed to a relative destabilization of the reactants (ATP and water) and relative stabilization of the products (ADP = Pi). Specifically

  • The reactants can not be stabilized to the same extent as products by resonance due to competing resonance of the bridging anhydride O's.
  • The charge density on the reactants is greater than that of the products
  • Theoretical studies show that the products are more hydrated than the reactants.

The DGo for hydrolysis of ATP is dependent on the divalent ion concentration and pH, which affect the the stabilization and the magnitude of the charge states of the reactants and products.



Carboxylic acid anhydrides are even more unstable to hydrolysis than ATP (-20 kcal/mol), followed by mixed anhydrides (-12 kcal/mol), and phosphoric acid anhydrides (-7.5 kcal/mol). These molecules are often termed "high energy" molecules, which is somewhat of a misnomer.  They are high energy only in relation to the energy of their cleavage products, such that the reaction proceeds with a large negative DGo.


How can ATP be used to drive thermodynamically unfavored reaction? First consider how the hydrolysis of a carboxylic acid anhydride, which has a DGo = -12.5 kcal/mol can drive the synthesis of a carboxylic acid amide, with a D Go = + 2-3 kcal/mol. The link below shows the net reaction, (anhydride + amine --> amide + carboxylic acid), which can be broken into two reactions: hydrolysis of the anhydride, and the synthesis of the amide.


Now consider the reaction of glucose + Pi to form glucose-6-P. In this reaction a phosphoester is formed, so the reaction would proceed with a positive DGo = 3.3. Now if ATP was used to transfer the terminal (gamma) phosphate to glucose to form Glc-6-P, the reaction proceeds with a DGo = -4 kcal/mol. This can be calculated since DG is a state function and is path independent. Adding the reactions and the DGo's for glucose + Pi ------> glucose-6-P and
ATP + H2O -----> ADP + Pi gives the resultant reaction and
glucose + ATP -----> Glucose-6-P + ADP,
DGo = -4.

In most biological reactions using ATP, the terminal P of ATP is transferred to a substrate using an enzyme called a kinase. Hence, hexokinase transfers the gamma phosphate from ATP to a hexose sugar. Protein kinase is an enzyme which transfers the gamma phosphate to a protein substrate.

ATP is also used to drive peptide bond (amide) synthesis during protein synthesis.  From an energetic point of view, anhydride cleavage can provide the energy for amide bond formation.  Peptide bond synthesis is cells is accompanied by cleavage of both phosphoanhydride bonds in ATP in a complicated set of reactions that is catalyzed by ribosomes in the cells.  (This topic is considered in depth in molecular biology courses).  The figure below is a grossly simplified mechanism of how peptide bond formation can be coupled to ATP cleavage.


Phosphorylation reactions using ATP are really nucleophilic substitution reactions which proceed through a pentavalent intermediate. The rest of the ATP molecule is then considered the leaving group, which could be theoretically ADP or AMP as well. If water is the nucleophile, the reaction is also a hydrolysis reaction. These reactions are also called phosphoryl transfer reactions.

One last note. ATP exists in cells as just one member of a pool of adenine nucleotides which consists of not only ATP, but also ADP and AMP (along with Pi). These constituents are readily interconvertible.  We actually break down an amount of ATP each day equal to about our body weight. Likewise we make about the same amount from the turnover products. When energy is needed, carbohydrates and lipids are oxidized and ATP is produced, which can then be immediately used for motility, biosynthesis, etc. It is very important to realize that although ATP is converted to ADP in a thermodynamically spontaneous process, the process is kinetically slow without an enzyme. Hence ATP is stable in solution. However, its biological half-life is not long since it is used very quickly as described above. This recapitulates a theme we have seen before. Many reactions (like oxidation with dioxygen, denaturation of proteins in nonpolar solvent, and now ATP hydrolysis) are thermodynamically favored but kinetically slow. This kinetic slowness is a necessary but of course insufficient condition, for life.


Our main goal is to understand how oxidation reactions can lead to ATP synthesis. First let us consider ATP production under anaerobic condition, such as which often occurs during the fight or flight response. You know how terribly you feel when you run a 100 m dash. Your muscles feel horribly due to lactic acid buildup, and you know you can't seem to get enough dioxygen into your body. Under these conditions, a pathway called glycolysis (which you studied in biology) is active.  In this pathway, glucose, a 6 carbon hexose, is converted to two, 3C molecules - pyruvate. Only one oxidative step occurred up to this point, namely the oxidative phosphorylation of another 3C reactant in glycolysis,  glyceraldehyde-3-phosphate, to 1,3-bisphosphglyercate, a mixed anhydride (see link below for mechanism). The oxidizing agent is NAD+ and the phosphorylating agent is NOT ATP but rather Pi. The enzyme is named glyceraldehyde-3-phosphate dehydrogenase.  It contains an active site Cys, which helps explain how the enzyme can be inactivated with a stoichiometric amounts of iodoacetamide.  A general base in the enzyme abstracts an H+ from Cys, which attacks the carbonyl C of the glyceraldehyde, forming a tetrahedral intermediate. Instead of the expected reaction (which would be the protonation of the alkoxide in an overall nucleophilic addition reaction at the aldehyde), a hydride leaves from the former carbonyl C to NAD+ in an oxidation step. Notice, this is a two electron oxidation reaction similar to seen in alcohol dehydrogenase.  An acyl-thioester intermediate has formed, much like the acyl intermediate that formed in Ser proteases. Next inorganic phosphorous, Pi,  attacks the carbonyl C of the intermediate in a nucleophilic substitution reaction to form the mixed anhydride product, 1,3-bisphoshphoglycerate. Although we have formed a mixed anhydride, we cleaved a sulfur ester, which is destabilized with respect to its hydrolysis products (since the reactant, the thioester, is not stabilized by resonance to the extent of regular esters owing to the poor donation of electrons from the larger S to the carbonyl-like C.) In the next step, catalyzed by the enzyme phosphoglycerate kinase, ADP acts an a nucleophile which attacks the mixed anhydride of the 1,3-bisphosphoglyerate to form ATP. Note that the enzyme is name for the reverse reaction. We have coupled oxidation of an organic molecule (glyceraldehyde-3-phosphate) to phosphorylation of ADP through the formation of a "high" energy mixed anhydride, 1,3-bisphosphoglycerate.

The linkage between oxidation of glyceraldehyde-3-phosphate and the phosphorylation of ADP by 1,3-bisphosphoglycerate can be artificially uncoupled by adding arsenate, which has a similar structure as phosphate.  The arsenate can form a mixed anhydride at C1 of glyceraldehyde-3-phosphate, but since the bridging O-As bond is longer and not as strong as in the mixed anhydride, it is easily hydrolyzed.  This prevents subsequent transfer of phosphate to ADP to form ATP.



Under anaerobic conditions, glucose is metabolized through glycolysis which converts it to two molecules of pyruvate. Only one oxidation step has been performed when glyceraldehyde 3-phospate is oxidized to 1,3-bisphosphoglycerate. To regenerate NAD+ so glycolysis can continue, pyruvate is reduced to lactate.   These reactions take place in the cytoplasm of the cell.


A quick glance reveals that we have taken glucose a small fraction along the way of oxidizing every carbon in it to CO2 and H2O. The complete oxidation happens under aerobic condition when the glycolytic pathway is followed by the Kreb's cycle. The main oxidizing agent used during aerobic metabolism is NAD+ which get converted to NADH. Unless the NAD+ can be regenerated, glycolysis and the Kreb's cycle will grind to a halt. Luckily, under these conditions we are actually continually breathing one of the best oxidizing agents around, dioxygen. NADH is oxidized back to NAD+ not directly by dioxygen, but indirectly as electrons flow from NADH through a series of electron carriers to dioxygen, which gets reduced to water. This process is called electron transport.  No atoms of oxygen are incorporated into NADH or any intermediary electron carrier. Hence the enzymes involved in the terminal electron transport step, in which electrons pass to dioxygen, is an oxidase.  The enzymes of the Kreb's cycle and electron transport are localized in mitochondria.

Figure:  mitochondria

By analogy to the coupling mechanism under anaerobic conditions, it would be useful from a biological perspective if this electron transport from NADH to dioxygen, a thermodynamically favorable reaction (as you calculated in the last study guide - a value of about -55 kcal/mol), were coupled to ATP synthesis.  It is!  For years scientist tried to find a high energy phosphorylated intermediate, similar to that formed by glyceraldehyde-3-phosphate dehydrogenase in glycolysis, which could drive ATP synthesis (which likewise occurs in the mitochondria.  None could be found. A startling hypothesis was put forward by Peter Mitchell, which was proven correct and for which he was awarded the Nobel Prize in Chemistry in 1978. The immediate source of energy to drive ATP synthesis was shown to come not from a phosphorylated intermediate, but a proton gradient across the mitochondrial inner membrane. All the enzymes complexes in electron transport are in the inner membrane of the mitochondria, as opposed to the cytoplasmic enzymes of glycolysis.  A pH gradient is formed across the inner membrane occurs in respiring mitochondria. In electron transport, electrons are passed from mobile electron carriers through membrane complexes back to another mobile carrier. Initially, NADH shuttles electrons (2 electron oxidation, characteristic of NAD+/NADH), to a flavin derivative, FMN, covalently attached to Complex I. The reduced form of FMN then passes electrons in single electron steps (characteristic of FAD-like molecules, which can undergo 1 or 2 electrons transfers) through the complex to the lipophilic electron carrier, ubiquinone, UQ.

Figure:  lipophilic electron carrier, ubiquinone, UQ

This then passes electrons through Complex III to another mobile electron carrier, a small protein, cytochrome C. Then cytochrome C passes electrons through complex IV, cytochrome C oxidase, to dioxygen to form water. At each step electrons are passed to better and better oxidizing agents, as reflected in their increasing positive standard reduction potential. Hence the oxidation at each complex is thermodynamically favored.


Complex II (also called succinate:quinone oxidoreductase) is a Kreb cycle enzyme that catalyzes the oxidation of succinate to fumarate by bound FAD (hence its other name: succinate dehydrogenase).  It is not involved in flow of electrons from NADH to dioxygen described above but passes electrons from the reduced succinate to ubiquinone to form fumarate and reduced ubiquone which then can transfer electrons to cytochrome C through Complex III.  The crystal structure of this complex has recently been solved by Yankovskaya et al. who have shown that the arrangement of the redox-active sites in the complex minimizes potential oxidation of bound FADH2 by dioxygen, minimizing production of harmful reactive oxygen species like superoxide.



At each complex, the energy released by the oxidative event is used to drive protons through each complex from the matrix to the intermembrane space of the mitochondria, and is not used to form a high energy mixed anhydride as we saw in the glyceraldehyde-3-phosphate dehydrogenase reaction. The actual mechanism of proton transfer is unclear.


How is this proton gradient coupled to ATP synthesis? Another mitochondrial inner membrane complex, FoF1ATPase, also called ATP synthase or complex V,  is found in the inner mitochondrial membrane.

Figure:  FoF1ATPase, also called ATP synthase

It contains two domains, a transmembrane proton channel, and a enzymatic domain which can either synthesize or hydrolyze ATP.  As protons stream through the membrane pore, conformational changes, probably mediated by concerted changes in amino acid side chain pKa's. cause the protein to synthesize ATP. Based on kinetic and structural data, Boyer devised an innovative hypothesis for the mechanism of ATP synthesis, which has been supported by recent structural data.  In this model the enzyme, which has multiple subunits, has 3 sites for ATP binding, named L, O, and T. The L or Loose site, binds ATP loosely, the T or Tight site binds it tightly, while the O or Open site does not bind ATP.  Although the DGo for ATP synthesis in solution is +7.5 kcal/mol, it appears the DGo for bound ADP + Pi ----> bound ATP is about 1. Hence the reaction is readily reversible. The difficulty lies in dissociating the bound ATP from the complex. Initially, ADP and Pi bind to the L site. A conformational change occurs, switching the site from L to T, and concomitantly, a T site with ATP bound to an O site which promotes ATP departure. Since the T site has ADP and Pi bound, but has high affinity for ATP, it promotes the synthesis of ATP at that site. This reflects the idea that enzymes bind the transition state (which presumably looks more like ATP than ADP and Pi) more tightly than the substrate. ADP and Pi bind to the newly formed L site which promotes the switch from the T to O site, releasing ATP from the enzyme.

It should now be clear why the enzymes for oxidative phosphorylation in aerobic conditions are membrane bound. Only in this way could a proton gradient be established. Protons must be vectorially transferred in one direction only for a gradient to be established!

Figure:  Overview of metabolism: Aerobic and Anerobic Generation of NADH, Regeneration of NAD, and Coupling Oxidation/Phosphorylation

Aerobic ATP production can be uncoupled from electron transfer, as we saw with arsenate uncoupling of ox/phos in aneraobic metabolism in glycolysis.  In that case, the energy sources driving ATP synthesis was removed through hydrolysis of the mixed carboxylate/arsenate anhydride.  In aerobic metabolism, the energy source is the proton gradient.  If this gradient could be artificially collapsed, ATP synthesis would stop, but electron transport (oxidation of NADH through formation of water from dioxygen) would continue.  2,4-dinitrophenol can collapse the proton gradient and act as an uncoupler.  In the low pH milieu of the intermembrane space, this weak acid would be protonated.  It is also sufficiently nonpolar so as to have reasonable bilayer permeability.  When it reaches the higher pH matrix, it can deprotonate.  The net effect is to shunt protons through the intermembrane and not through the F0F1ATPase. 

Figure:  Uncoupling Aerobic Ox/Phos

Recent Confirmation of the Boyer Hypothesis

More recent studies by Noji et al. have shown that ATP synthase, also called FoF1ATPase, is a rotary enzyme. A recent review in Science (1998 December 4; 282: 1844-1845) discuss these amazing result. This enzyme is found in the inner membrane of mitochondria, the analogous thylakoid membranes of chloroplasts, and in the cell membrane of bacteria. The enzyme consists of two parts, the membrane bound Fo which is a proton pore, and the F1 part which has catalytic activity. The enzyme is reversible. If protons flow down a concentration gradient through Fo, ATP is synthesized by F1. Alternatively, ATP hydrolysis by F1 leads to transport of protons through Fo and against a concentration gradient. Isolated F1 can only break down ATP, and not synthesize it.   The F1 subunit (with quaternary structure of a3b3 forming a ringed structure with central cavity) is about 80 angstroms from the Fo subunit and both are connected to a rod-shaped g subunit which spans the center of the a3b3 ring. Energy transduction (necessary to capture the negative free energy change associated with the collapse of the proton gradient to drive the positive free energy change for ATP synthesis) occurs between the two subunits. Hence Noji investigated the structural changes in the g subunit, wishing to get direct experimental evidence for Boyers three-state conformational model (L-O-T) for ATP synthesis.

Figure:  Boyers three-state conformational model (L-O-T) for ATP synthesis

In this model, the F1 subunit was postulated to exist in three states: an O - open - state with very low affinity for substrates and has no catalytic activity; a L - loose - state with low affinity for substrates and also no catalytic activity, and a T - tight - tight state with high affinity for substrates and with catalytic activity. The F1 subunit consist of three a and three b subunits, which have three conformations, bind substrate, and have catalytic activity. The collapse of the proton gradient (i.e. the proton-motive force) causes the g subunit to rotate like a crankshaft relative to the F1 subunit, forcing the b subunit to change conformation from the T to the O (releasing ATP) and then the L (binding ADP and Pi). The g subunit does not appear to undergo any significant conformational change on ATP hydrolysis as evidenced by tritium exchange studies of amide protons. To prove that the g subunit rotates, you'd have to observe a single molecule. Since the g subunit was too small, Noji covalently attached a fluorescein-labeled protein filament called actin to the g subunit (near where Fo would bind). He then fixed the whole F1 molecule to a glass slip through the a3b3 part, immobilizing that part of the molecule. The g subunit was free to rotate, which could be detected by observing the fluorescence under a fluorescent microscope from the attached actin filament.

Figure:  fluorescein-labeled protein filament called actin to the g subunit

The result were amazing. The actin filament rotated only in the presence of ATP. It rotated only counterclockwise, and continued for 10 minutes. This demonstrated that the motion was not random, but a specific motion of the g subunit. At extremely low concentration of ATP, rotation occurred only in 120o  increments, implying one step per molecule of ATP hydrolyzed. (Remember the b subunits are separated by 120o ). As the rotation occurs, there is viscous resistance to movement of the actin filament. He calculate that for a single 120o  step caused by hydrolysis of a single ATP molecule, the amount of work was 80 piconewton which is about the free energy of hydrolysis of a single ATP molecule.  Incidentally, Boyer was recently award the Noble prize in Chemistry in 1997 for his work.

In more recent work (Nature, 410, 898 (2001)),   Noji and his colleagues replaced the actin filament with a smaller colloidal gold bead (40 nm diameter) with less frictional resistance to movement and used laser light scattering to probe the rotation of the fixed F1 subunit through the g subunit. 

Figure:  smaller colloidal gold bead (40 nm diameter) with less frictional resistance

At low [ATP], the motor rotates in 120o  steps. At high [ATP], the rotation rate becomes continuous and saturates (with Michaelis/Menten kinetics) at 130 revolutions per second. 

Figure:  rotation rate becomes continuous and saturates

How does the pH Gradient collapse lead to ATP synthesis?

See the link below and the following text to understand the answer to this question.

Figure:  Coupling Proton Flow in F0 to Conformation Change

The mechanism of proton transfer through Fo has been clarified by Rastogi and Girvin (1999) who studied the enzyme in E. Coli  which have no mitochondria.  The FoF1ATPase resides in the cell membrane, with the F1 subunit situated in the cytoplasm, where ATP occurs.  Protons flow into the cytoplasm from the periplasm, the space between the plasma membrane and the cell wallClues come from the structure of the F0 membrane proton channel, which is a multimeric protein (ab2c12).  The c ring contacts the a chain in F0 and the g subunit of F1.  An Asp 61 (D61) buried in the cell membrane in the E. Coli c subunit moves protons at the interface between the a and c subunits.  It appears to be able to transfer a proton to Arg 210 of the a subunit.  In between these two protons donors/acceptors are a swath of hydrophilic amino acids, providing a conduit for proton transfer from the periplasm to the cytoplasm.   A set of polar residues entirely within subunit a, including Gln 252, Asn 214, Asn 148, Asp 119, His 245, Glu 219, Ser 144 and Asn 238 provide the path.  Protons probably flow from the periplasmic space down the hydrophilic path to Arg 210 of the a subunit and to Asp 61 of the c subunit.   Arg 210 of subunit a lies between two  Asp 61 side chains on two different c subunits of the c12.  In the resting state, one of the Asp is protonated, while the other is not.  When a proton is passed to the unprotonated Asp, a conformational change in the protonated c subunit occurs.  This leads to changes in c subunit interactions which seems to ratchet the c12 core.  Since the c12 oligomer  contacts  the g subunit connecting the Fo stalk and F1 ATPase units, the g subunit rotates, leading to sequential conformational changes in each of the 3 contacted  (ab)2 dimers of the F1 enzyme. This leads to changes in ATP affinity through cycling each through the L, O, and T conformations. 


Experimental evidence shows that it can. The FoF1ATPase complex can be removed from membranes and placed in a liposome into which ADP and Pi have been encapsulated. The pH of the outside of the vesicles is then lowered several pH units. Under these circumstances, ATP is generated inside the vesicle proving that a gradient alone can drive its synthesis.

Mathematical analyses show that it can as well. Consider a typical pH gradient (-1.4 pH units) across the inner membrane of respiring mitochondria (with the outside having a lower pH than inside making the inside more depleted in protons). Clearly there is a chemical potential difference in protons across the membrane. However, another factor determines the thermodynamic driving force for proton translocation across the membrane. A transmembrane potential exists across the inner membrane of the mitochondria, as it does across most membranes. The source of the membrane potential will be discussed in signal transduction chapter. The inside is more negative than the outside, giving the membrane a transmembrane electrical potential. of about -0.14 V. Clearly, protons would be attracted to the other side of the membrane (into the matrix) by this potential difference, which then augments the chemical potential difference as well. A simple mathematical derivation shows that indeed, a proton gradient can supply enough energy for ATP synthesis, especially when coupled to a transmembrane electrical potential.

Figure:  A simple mathematical derivation

The sum of the electrical and chemical potentials are called the electrochemical potential, which when divided by nF gives the proton motive force.

Note: In the above discussion, we dealt with two different proton translocating methods: 

Figure:  two different proton translocating methods

  1. Complex I, III, and IV, which couple uphill proton movement (from the higher pH matrix to the lower pH intermembrane space)  to oxidation (NADH + O2 to NAD+ + H2O). 
  2. Downhill movement of protons through F0F1 ATPase which couples to ATP synthesis by the enzyme. 

Feeding and Fasting: The Regulation of storage and breakdown of glucose and lipids - The role of PPARs

We have spend little time discussing the detailed anabolic and catabolic pathways of metabolism.  That is the topic of a another biochemistry course.  However, it should be clear that the one pathway should be activated and the other inhibited, depending on the energy state of the individual.  In the well fed state (high levels of carbohydrates and lipids), glycogen, triacylglycerides, and fatty acids synthesis should be activated, while glycogen breakdown (glycogenolysis), mobilization of triglycerides reserves (breakdown of TAGs to form free fatty acids), and fatty acid oxidation should be minimized.  In the fasting state, the opposite pathways should be activated.  The regulatory control of these opposing processes is complicated but PPARs have been shown to have a major role.  PPARs (peroxisome proliferator-activated receptors) are nuclear receptors that are ligand-gated transcription factors.  These proteins were initially discovered to be the binding target of small synthetic drugs called peroxisome proliferators. Later the relevant physiological ligands were found to include long chain polyunsaturated fatty acids, oxidized fatty acids, and eicosonoid derivatives of arachidonic acid (20:4D5,8,11,14).  PPAR, in the presence of ligand binds a second protein, the retinoid X receptor (RXR) which binds 9-cis-retinoic acid).  The heterodimer binds to peroxisome proliferator response element in the promoter region of genes involved in lipid transport and metabolism, and activates their transcription.  Given these facts, common chronic diseases with lipid abnormalities (cardiovascular disease, diabetes, obesity) would be expected to be affected by PPARs.  There are three types of PPARs:  a, b, and g.  Only the major two types, a and g, will be discussed.   

PPAR Type location ligand activator effects
a brown adipose tissue, liver (some in kidney, heart, and skeletal muscle long chain unsaturated fatty acid like linolenic acid, oxidized fatty acid, eicosanoids   (8S-HETE, LT B4 fatty acid catabolism - FA transport, FA oxidation in peroxisomes and mitochondria,
 g adipose cells, some in colon 15-deoxy-D-prostaglandin J2   storage of fatty acids - lipoprotein lipase, adipocyte FA binding protein, FA transport; acyl CoA synthase

Fatty acids are oxidized when food is scarce, but are stored as triacylglycerides when they are abundant.  PPARs a and g have differential effects in the fed and fasting states:

Organ Fed:  Synthesize FA, triacylglycerides. CHO and fat in circulation  Increased PPAR Fasting: oxidize FA, break down triacylglycerides  Increased PPAR


Glc taken up by liver where it can be stored as glycogen.  If glycogen reserves are high, Glc is funneled through glycolysis to pyruvate then to acetyl-CoA.  Acetyl CoA then is used in the synthesis of fatty acid, which are esterifed to glycerol to form TAGs.  These leave liver as VLDL (very low density lipoprotein).  Sterol response element binding protein (SREBP) levels increase, leading to increase in transcription of genes involved in above processes. 

FAs oxidized to Acetyl-CoA.  Ketone bodies increase.  Stimulated by increased expression of PPAR-a in fasting state.  Increased FAs in liver (headed toward oxidation) might bind to PPAR-a and increase its activity.  (abcosq)



SREBP and PPAR-g levels increases (from insulin signaling).  Also SREBP activates PPAR-g gene transcription.  Lead to uptake of Glc and FA into fat cells (through stimulation of breakdown of blood TAGs, to fatty acids which can be imported into fat cells.  Glc through glycolysis to glyceraldehyde 3P which with FAs are converted to TAGs.  Increased TAGs lead to leptin release by adipocytes.  (This hormone leads to decreasing storage of TAGs. _(AG) SREBP and PPAR-g levels lows.   TAGs converted to glycerol and FA, mostly for export;  Some however reesterifies from FA and glycerol made reverse of glycolytic pathway, called gluconeogenesis; Transcription of an important enzyme in this pathway, PEPCK, is activated under control of PPAR-g

Drugs that bind to and either mimic (agonist) PPAR -a or g effects are useful therapeutically in conditions characterized by lipid abnormalities (diabetes, cardiovascular disease).  Drugs that bind to and activate PPAR-g (Rezulin, Avandia) can lower blood glucose levels and are used to treat type II diabetes.  Drugs that activate PPAR-a (fibrates like gemfibrozil) can lower serum triglycerides (by stimulating liver fatty acid oxidation).  Both drugs ultimately lower serum lipids. 

PPARs also have an effect on plasma lipoprotein (LDL, HDL) levels.  Both also might have a role in inflammation, which can promote cardiovascular disease.  Fibrates, which interact with PPAR-a , appear to inhibit the inflammatory response mediated by the immune system by decreasing the release of protein "hormones" or cytokines, from stimulated immune cells. 

Biochemistry - Where molecules become life...