Carbohydrate Metabolism

INTRODUCTION

Purpose: To review and reinforce your knowledge of the reactions of glycolysis, gluconeogenesis, the pentose phosphate pathway and the tricarboxylic acid (Krebs) cycle, as well remind you about some vitamin-coenzyme connections.

Recall Objectives:

1. Know the "bottom lines" of glycolysis, gluconeogenesis, pentose phosphate, the TCA cycle and the pyruvate dehydrogenase reaction.
2. Reason from the pathways in clinical contexts and recognize the key regulatory steps in these pathways.
3. Recognize why the intermediates -- and the enzymes that act on them -- have the names that they do.
4. Apply knowledge of the pathways to clinical situations.
5. Describe the following reactions:
   Hexokinase Phosphofructokinase-1 Glyceraldehyde 3-phosphate dehydrogenase Pyruvate kinase Pyruvate dehydrogenase Isocitrate dehydrogenase α-ketoglutarate dehydrogenase Succinate dehydrogenase Glucose 6-phosphate dehydrogenase Pyruvate carboxylase Fructose 1,6-bisphosphatase Glucose 6-phosphatase
6. Identify the four functions of the pentose phosphate pathway.
7. Associate coenzymes with the vitamins from which they are produced and list reactions these coenzymes participate in.
8. Distinguish between the concepts of coenzyme and vitamin.
9. Recognize why compounds -- and the enzymes that act on them -- have the names they do.

GLYCOLYSIS

For a good summary of the glycolytic pathway, check Devlin, Figure 15.6.  
Please note the structuring into the three stages: (a) Priming stage; (b) Splitting stage; (c) Oxidoreduction—phosphorylation stage.

Glycolysis is divided into 3 stages: 

Stage 1 (Priming stage)

Phosphorylation of glucose and conversion to phosphorylated fructose. This stage requires energy in the form of ATP.

Stage 2 (Splitting stage)

Cleavage of the 6-carbon phosphorylated fructose into two 3-carbon phosphorylated sugars.  

We have now converted a single 6-carbon glucose into two 3-carbon glyceraldehyde 3-phosphates.

Stage 3 (Oxidoreduction-phosphorylation stage)

The "payoff". Energy is generated in this stage.

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Energy Balance Sheet for glycolysis

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PYRUVATE DEHYDROGENASE

The acetyl-CoA thus produced can go into the TCA cycle or be converted into fatty acids, ketone bodies, or steroids.   NADH can be used to generate energy via electron transport: 2.5 ATP's.

TRICARBOXYLIC ACID (TCA) CYCLE

The TCA cycle only occurs under aerobic conditions; it generates energy in the form of GTP (equivalent to ATP), NADH, and FADH₂

For a picture of the TCA cycle, see Devlin, Figure 14.18.

Learning the TCA cycle is easier if you keep your carbons straight.

Starting with pyruvate, the cycle can be summed up as:

Pyruvate + 4 NAD⁺ + FAD + GDP + P_i —> 3 CO₂ + 4 NADH + 4 H⁺ + FADH₂ + GTP

PENTOSE PHOSPHATE PATHWAY

 For a picture of the pentose phosphate pathway, see Devlin, Figure 16.3.

Purpose 1: Sequester the high-energy electrons in dietary glucose

Purpose 2: Produce pentoses, such as ribose, for nucleotide synthesis

Purpose 3: Dispose of excess ribose

Purpose 4: Anti-oxidant defense

We live in an environment that produces a large amount of oxidation in our tissues. These oxidation reactions can damage our cells. The reducing power of NADPH makes it ideal as a co-factor for many of our anti-oxidant defense systems.   This is very important in RBCs which have to maintain the iron in hemoglobin in the reduced state. Note that lesions in the pentose phosphate pathway in RBCs can cause serious reactions to certain medications.

GLUCONEOGENESIS

 For a picture of gluconeogenesis, see Devlin, Figure 15.31

How is gluconeogenesis different?

The liver's job is to make sure that levels of blood glucose are sufficiently maintained to support brain and RBC function.  The actual levels of glucose can be regulated by the hormones insulin and glucagon.

Reactions

Gluconeogenesis is almost like glycolysis run in reverse.   However, there are three reactions in glycolysis that very strongly favor the glucose —> pyruvate direction.   In gluconeogenesis these reactions are replaced by others that favor the pyruvate —> glucose direction.

NUTRITIONAL ASPECTS: VITAMINS AND COENZYMES

A coenzyme is a small molecule that participates in an enzymatic reaction without really getting used up.   (It may get oxidized or reduced but that is easily reversible).   Often the structure of coenzymes is somewhat complex which means that our bodies do not have the enzymes to put them together and hence we consume the complex part of the coenzyme as a vitamin.   Then we often add something to the vitamin, sometimes a nucleotide, and it becomes a coenzyme.   Many of the enzymatic reactions discussed above use coenzymes derived from vitamins.   The table below summarizes this information:

Just for Fun: Why Does the TCA Cycle Produce GTP?

GTP is energetically equivalent to ATP, so why doesn't the TCA cycle just produce ATP in the succinyl CoA synthetase reaction instead of GTP, since ATP is produced in all the other energetic reactions in glycolysis and electron transport?   The GTP produced in the TCA cycle may actually be a very ancient molecular "fossil".   It is thought by some scientists that the early earth had a reducing atmosphere, lacking molecular oxygen and being rich in CO₂.   This was when the first cells appeared.   Look at the TCA cycle and pyruvate dehydrogenase and run them backwards in your mind instead of forward as happens in our bodies today.   We could start with an acetate group, and then pyruvate dehydrogenase would add a CO₂ to it while pyruvate carboxylase would add another CO₂ (it still does) and you would get oxaloacetate.   Now, run the TCA cycle backwards and you will end up with the 6-carbon citrate.   It is thought by some that these central metabolism pathways originated as a way to trap carbon and use it to build compounds with larger carbon skeletons by binding CO₂.   The pyruvate dehydrogenase reaction and the TCA cycle running backward could have been fueled by electrons from the reducing environment and also may have required GTP for energy.   At the time of the first cell, protein synthesis, which also requires GTP for energy, may have been getting started, as well as polymerization of certain filaments which even today require GTP.   It may be that at the beginning, both GTP and ATP were equally available for energy and that the succinyl CoA synthetase reaction happened to choose GTP and that reaction is still with us today, billions of years later, even though we run the TCA cycle clockwise (forward) instead of backwards.

Quick Check

References and Credits

Images

All images created with resources in the public domain on behalf of the Undergraduate Medical Education office, School of Medicine, University of Texas Health Science Center at San Antonio except as noted below.

Page 1

"Glucose" (2011) From the appendix of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011). (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/p1123_2

Page 2

"Stage 1" Adapted from Chapter 15 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011). (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig15_6

"Stage 2" Adapted from Chapter 15 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011). (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig15_6

"Stage 3" Adapted from Chapter 15 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011). (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig15_6

Page 3

"Drag and Drop Exercise" Adapted from Chapter 15 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011). (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig15_6

Page 4

"Tricarboxylic Acid Cycle" [9 images in presentation] Adapted from Chapter 14 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011) (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig14_18

Page 5

"Pentose Phosphate Pathway" [Presentation A, 4 images] Slides created using images in the public domain.

"Pentose Phosphate Pathway" [Presentation B, 4 images] Slides created using images adapted from Chapter 16 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011) (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig16_3

"Purpose 2" Image adapted from Chapter 16 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011) (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig16_3

"Purpose 3" Image adapted from Chapter 16 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011) (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig16_3

Page 6

"Gluconeogenesis" [Photo album, 13 images] Images adapted from Chapter 15 of Textbook of Biochemistry with Clinical Correlations, 7th Edition. (2011) (T.M. Devlin, Ed.). Retrieved from http://online.vitalsource.com/books/9780470912096/id/fig15_31

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