Copyright © 2006 by Elsevier, Inc. Adenosine triphosphate (ATP) - the central link between energy-producing and energy-using systems of the body Figure 67-1; Guyton & Hall

Copyright © 2006 by Elsevier, Inc. Downloaded from: StudentConsult (on 1 March :39 PM) © 2005 Elsevier ATP Structure

Copyright © 2006 by Elsevier, Inc. Phosphate Terminology Kinase –adds a phosphate phosphatase –removes a phosphate phosphorylase –splits a compound by adding a phosphate (analagous to hydrolysis, but uses phosphate instead of water)

Copyright © 2006 by Elsevier, Inc. Glucose Transport Into Most Cells Down a concentration gradient by facilitated diffusion, –i.e. a carrier is required but energy is not There are many different carriers. The most important and commonly studied are –GLUT-1, does not require insulin note that most post-absorptive glucose uptake by cells does not require insulin –GLUT-4, insulin dependent

Copyright © 2006 by Elsevier, Inc. Glycolysis Glucose Fructose 1,6- diphosphate (PP) Dihydroxyacetone Phosphate (DHAP) Glyceraldehyde 3-phosphate (GA 3-P) 2 ATP 2 Pyruvic Acid 4 ATP 2 NADH + 2H Net Output: 2 pyruvate 2 NADH + H (4 H’s) 2 ATP 4 ADP 2 NAD+

H 3 C - C - C O O OH H 3 C - C - S - CoA O Transport into Mitochrondrion NADH + H CO2CO2 HS - CoA Go from 3-C pyruvate to a 2-C Acetyl CoA Formation of Acetyl CoA from Pyruvic Acid Remember, there are 2 pyruvates per glucose molecule! CO 2 Pyruvic Acid Acetyl CoA Copyright © 2006 by Elsevier, Inc.

Acetyl CoA C - C - C - C O O OH O HO Oxaloacetate (4-carbon) Citrate (6-C) NADH + H CO 2 FADH 2 ATP H 3 C - C - S - CoA O Remember... 2 of these per molecule of glucose, so double the outputs of the TCA shown here. Copyright © 2006 by Elsevier, Inc.

One molecule of glucose yields... Glycolysis –2 NADH –2 ATP Pyruvate to Acetyl CoA conversion –2 NADH (because there are 2 pyruvates) Citric Acid cycle (numbers are for 2 pyruvates going through) –6 NADH –2 FADH 2 –2 ATP Total: 10 NADH, 2 FADH 2, and 4 ATP

Copyright © 2006 by Elsevier, Inc. Electron Transport, Making ATP Each NADH + H yields 2 electrons –Electron transport along the cytochrome chain enables establishment of an electrochemical H+ gradient along the inner mitochondrial membrane. Hydrogen movement down this gradient, through the ATP synthetase, provides the energy for conversion of ADP to ATP. Each electron pair from each NADH + H can provide enough energy for production of 3 ATP –electron pair from FADH2 yield 2 ATP

Copyright © 2006 by Elsevier, Inc. Downloaded from: StudentConsult (on 1 March :39 PM) © 2005 Elsevier Chemiosmosis

Copyright © 2006 by Elsevier, Inc. ATP Synthase

Copyright © 2006 by Elsevier, Inc. One molecule of glucose yields... Glycolysis –2 NADH + 2H –2 ATP Pyruvate to Acetyl CoA conversion –2 NADH + 2H Citric Acid cycle –6 NADH + 6H –2 FADH 2 –2 ATP Total: 38 ATP, which yields ~ 456 kcal 6 ATP 18 ATP 4 ATP

Glucose Galactose Fructose Glucose-6-P Fructose-1,6-PP Fructose-6-P DHA-P GA 3-P Galactose-1-P Glucose-1-P glucokinase (liver) hexokinase Fructose-1-P fructokinase galactokinase Copyright © 2006 by Elsevier, Inc.

Glucose Galactose Fructose Glucose-6-P Fructose-6-P Glucose-1-P glucose-6-phosphatase Because the liver has this enzyme, it can convert the other monosaccharides into glucose for export. (Renal tubular and intestinal epithelial cells also have this enzyme) Phosphorylation of the monosaccharides upon entering cells of the body “traps” it there for use. The G-6-P enzyme is needed for tissues that send glucose to other parts of the body. Copyright © 2006 by Elsevier, Inc.

Glucose 1-P Glucose 6-P Glycolysis UDP -Glucose Glycogen Glucose From Gluconeogenesis From the Blood Glycogenesis & Glycogenolyis Glycogenolysis Glycogenesis Copyright © 2006 by Elsevier, Inc.

The Lactate Story The NADH formed from oxidizing glucose eventually gets oxidized back to NAD+ in the mitochondria. –(the result of giving the electrons to electron transport chain) NAD+ is needed to keep oxidizing glucose. In exercise (once the anaerobic threshold is crossed), NAD+ isn’t re-formed fast enough, so low levels threaten to stop glycolysis and ATP production. The main reason to form lactate is to regenerate the NAD+ needed to continue oxidizing glucose.

Glyceraldehyde P 1,3 - Diphosphoglycerate Lactate Pyruvate NAD+ NADH (oxidized) (reduced) reduction reaction oxidation reaction GLYCOLYSIS Copyright © 2006 by Elsevier, Inc.

The Fate of Lactate Lactate is transported to the liver for conversion back to pyruvate and then, via gluconeogenesis, to glucose. –Why would muscle transport lactate to the liver for conversion back to pyruvate? NAD+ is needed for that step, and the point of making lactate in the first place was because NAD+ was too low. Lactate is in a sense a “storage form” of NADH, because when it gets oxidized back to pyruvate, NADH is formed. The glucose is released and taken up by the active muscle.

Copyright © 2006 by Elsevier, Inc. More on Lactate Reconversion of Lactic Acid: Why does excess ATP cause excess pyruvate to be converted back to glucose? –This is because high ATP levels inhibit glycolysis and actually promote the reverse, i.e. gluconeogenesis. Lactic Acid and the Heart –The very high blood flow and O 2 levels mean no shortage of NAD+ so any lactate that is formed can be oxidized readily to pyruvate. –Significant lactic acid is formed in the heart only during ischemia. –Lactate Dehydrogenase (LD) has a very low affinity for pyruvate in the heart, also explaining why little lactate is formed normally. However, cardiac LD has high affinity for lactate, hence the ability of the heart to utilize lactate from the circulation during exercise. in “white” skeletal muscle, LD has a high affinity for pyruvate.

Copyright © 2006 by Elsevier, Inc. Control of Glucose Oxidation fructose 6-P fructose 1,6-diphosphate Phosphofructokinase ATP ADPcitrate glucagon Pyruvate kinase NADH Pyruvate PEP Acetyl CoA pyruvate dehydrogenase Pyruvate Mitochondrion citrate formation (+ other steps) +

Copyright © 2006 by Elsevier, Inc. Effects of Epinephrine and Glucagon Glycogen Glucose-1- P “Glucose” Glycogen Glycogen Synthase INACTIVE INACTIVE (D) Epinephrine/ Glucagon cAMP-dependent protein kinase Inactivates this by adding Activates this by adding P Phosphorylase a active P P P +

Phosphorylase a active Glycogen Glucose-1- P Phosphorylase Phosphatase active phosphorylase b kinase Epinephrine/ Glucagon cAMP Epinephrine and Glucagon stimulate glycogen breakdown ultimately by adding a to and activating glycogen phosphorylase (phosphorylase a). Phosphorylase b inactive cAMP-dependent protein kinase Phosphorylates and activates this enzyme P P P P Copyright © 2006 by Elsevier, Inc.

Final Enzymes for Glycogen -esis and -olysis Glycogen Glucose-1-P “Glucose” Glycogen Phosphorylase a active P Glycogen Synthase active (I) Glycogenolysis Glycogenesis Note that the enzyme for glycogenolysis is activated when it is phosphorylated (i.e. has a phosphate added ), but the enzyme for glycogenesis is inhibited by phosphorylation. (Phosphorylase b is the inactive form) P