Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online

CHAPTER 8 - OXIDATION/PHOSPHORYLATION

C:  ATP AND OXIDATIVE PHOSPHORYLATION

BIOCHEMISTRY - DR. JAKUBOWSKI

 04/15/16

Learning Goals/Objectives for Chapter 8C: 

After class and this reading, students will be able to

  • explain reasons for the strongly exergonic hydrolysis of carboxylic acid anhydrides, phosphoric acid anhydrides, mixed anhydrides, and analogous structures and give approximate  values for the ΔG0 of hydrolysis of them;
  • identify from Lewis structures molecules whose hydrolytic cleavage are strongly exergonic;
  • explain how the exergonic cleavage of phophoanhydride bonds in ATP can be coupled to the endergonic synthesis of macromolecules like proteins;
  • draw mechanisms to show how oxidation and phosphorylation reactions are coupled in anaerobic metabolism through the productions of a mixed anhydride catalyzed by the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase;
  • explain how arsenate can double oxidation and phosphorlyation reactions in glycolysis
  • explain how NAD+ can be regenerated from NADH in anaeroboic condition to allow glycolysis to continue;
  • explain the general flow of electrons from NADH to dioxgen through a series of mobile and membrane protein bound electron acceptors in electron transport in the mitochondria inner member.
  • explain with picture diagrams how oxidation and phosphorylation reactions (to produce ATP) are coupled in aerobic metabolism through the generation and collapse of a proton gradient in the mitochondria;
  • draw pictures diagrams explaining the structure of F1F0ATPase in the inner mitochondria member and explain using the picture how ATP synthesis is coupled to protein gradient collapse
  • write an equation for the electrochemical potential and use it to calculate the available ΔG0 for ATP production on proton gradient collapse, given typical values for ΔpH and ΔE across the membrane 

C13.  PPARs and the Regulation of Metabolism

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 (20:4Δ5,8,11,14).  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:  α, β, and γ.  Only the major two types, α and γ, will be discussed.   

PPAR Type location ligand activator effects
α 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,
 γ 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 α and γ 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
Liver

(PPAR-α)

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-α in fasting state.  Increased FAs in liver (headed toward oxidation) might bind to PPAR-α and increase its activity.  (αβcosθ)
Adipocyte

(PPAR-γ)

 SREBP and PPAR-γ levels increases (from insulin signaling).  Also SREBP activates PPAR-γgene 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-γ 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-γ

Drugs that bind to and either mimic (agonist) PPAR -αorγ 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. 

Pathways for PPAR-mediated activation of gene transcription.

Pathway for PPAR-αmediated activation of gene transcription

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