Carbohydrate Metabolism II

how is pyruvate transported into mitochondria?

proton symporter

Pyruvate dehydrogenase complex

- 3 enzymes located on the inner mitochondrial membrane

- Limiting step: pyruvate dehydrogenase (PDH)

- Complex involves B vitamins (pantothenic acid, thiamin, niacin, riboflavin)

What is the net effect of pyruvate oxidation?

decarboxylation and dehydrogenation of pyruvate with NAD+ serving as terminal hydrogen acceptor

= NADH and acetyl CoA

TCA cycle

- final oxidation pathway of all macronutrients to CO2 and H2O

- 90% of all energy from food released here

- mainly dehydrogenation reactions that generate NADH and FADH2

how much ATP is generated from NADH and FADH2?

NAD = 3 ATP, FAD = 2 ATP

oxaloacetate

combines with acetyl CoA to form citrate via citrate synthase, often limiting

(-) NADH, succinyl CoA

what does citrate regulate?

PFK

what is produced in the TCA cycle per pyruvate?

Net: 3 NADH + 1 FADH2 per pyruvate molecule (+ 1 ATP)

yield of 1 glucose

- 6CO2

- 4 ATP (2 from glycolysis, 2 from TCA)

- 10 NADH (2 glycolysis, 2 PDH, 6 TCA)

- 2 FAD

= 36-38 ATP

anaplerosis

- different substrates used to keep TCA cycle going (e.g. amino acids)

- ↑ Acetyl-CoA requires ↑ amounts of oxaloacetate (often limiting)

2 mechanisms for ATP formation

- Substrate level phosphorylation

- Oxidative phosphorylation

substrate level phosphorylation

- anytime we make ATP outside of oxidative phosphorylation

- molecules donating P to ADP (e.g. phosphocreatine, G-1-P, G-6-P)

oxidative phosphorylation

- NADH and FADH2 donate electrons

- electrons flow through complexes, getting oxidated

- pumps H+ from matrix to inner mitochondrial space, creating electrical gradient

- metabolic water and ROS produced

- gradient drives through ATP synthase (complex V), phosphorylating ADP

pentose phosphate pathway

- aka Hexose monophoshate shunt

- Pathway begins at G6P

- Generates intermediates not produced in other pathways (e.g. pentoses for nucleic acid synthesis, NADPH)

what is NADPH used for?

- Fatty acid biosynthesis

- Cell membrane functionality (RBC)

- Drug metabolism (liver)

gluconeogenesis

- Liver (primary site) and kidneys

- ↓ dietary CHO causes ↓ blood glu causes ↑ glucagon/epi causes ↑ glucogneogenesis

- Usually occurs during fasting, sometimes during diabetes

non-CHO sources for gluconeogenesis

- Lactate (Cori cycle)

- Pyruvate

- Alanine

- Glycerol

enzymes involved in reversal of glycolysis

- G-6-P reverses glucokinase

- Fructose 1,6-biPase reverses PFK

- *no enzyme to reverse pyruvate kinase (last step in glycolysis, PEP→ pyruvate)

reversal of pyruvate kinase

1. Pyruvate directly formed to oxaloacetate

2. Oxaloacetate converted to malate or aspartate instead

3. Malate is shuttled out of mitochondria

4. Malate converted to oxaloacetate

5. Formation of PEP (uses GTP)

how is fructose converted to glucose?

- undergoes rapid phosphorylation in the liver to F-6-P

- bypasses PFK

- reversal glycolysis steps and converted to glycogen or glucose*

effects of fructose on fat metabolism

- ↑ fatty acid synthesis

- ↑ re-esterification of fatty acids

- ↑ VLDL (↑ TG, LDL)

*Estimated only 10% of fructose goes to fat synthesis

how is galactose converted to glucose?

- phosphorylated to galactose-1-phosphate (uses ATP)

- UDP added

- converted to glycogen via glycogen synthase

4 ways to regulate CHO metabolism

1. allosteric regulation (via modulators)

2. covalent modification/induction by hormones

3. directional shifts in reversible reactions by changes in reactant or product concentration

4. translocation of enzymes (e.g. GLUT4)

dietary fibre

- Nondigestible CHO and lignin that are intact and intrinsic in plants

- e.g. cellulose, pectin, lignin, beta glucan

functional fibre

- Nondigestible CHO that have been isolated, extracted or manufactured and have been shown to have beneficial physiological effects in humans

- e.g. polyols, psyllium

parts of wheat kernel

- bran has insoluble fibre

- germ has nutrients, fat

- endosperm has some nutrients, mostly starch

fibre recommendations

- 38g men

- 25g women

are we meeting fibre recommendations?

naw

soluble vs insoluble fibres

*continuum

- soluble form gel better (e.g. pectin, gums, beta glucan)

- insoluble are roughage (e.g. cellulose, lignin)

how does fibre keep the gut healthy?

- stimulating peristalsis

- sloughing off old cells

- keeping things moving

effects of the gel formed by fibre

- delayed gastric emptying and digestion (via incretins)

- satiety

- Reduced mixing of contents with enzymes and reduced enzyme function (physical barrier)

- decreased nutrient diffusion rate

- altered transit time

how does fibre decrease nutrient diffusion rates?

- Changes (↑ viscosity) to mucin layer (watery layer on surface of microvilli)

- Reduced peristaltic movements

- "Missing" normal site of maximal absorption

what is fibre's effect on bile acids?

binds with bile and excretes it in fecal matter

why does reducing bile acid re-absorption lower cholesterol?

- bile acids are made from cholesterol

- getting rid of bile acids forces body to make more, using cholesterol

what effects does fibre have on bile acid pools?

- decreases cholesterol biosynthesis

- decreases HMG-CoA reductase- rate limiting enzyme of cholesterol synthesis, targeted by statins

how is fibre digested?

- Fermentation by bacteria

- occurs in the ascending colon

- Soluble/viscous fibres are more readily fermented

products of fibre digestion

lactate, SCFA (acetic, butyric, propionic)

effects of SCFA

- ↑ water and sodium absorption

- Mucosal cell differentiation and proliferation

- Provision of energy

- Acidification of luminal environment (pH determines what time of bacteria grows)

- Inhibition of cholesterol synthesis

- Improved colonic blood flow

- Enhanced immune function

- Trophic effects and prevention of abnormal cell populations

almond studies

only ~40% of calories from whole almonds are absorbed, less cell walls broken down due to fibre

why do whole grains reduce risk of colon cancer more than fruits/vegetables?

- polyphenol compounds in whole grains are bound to cell walls

- prevents/delays digestion, allowing for fermentation in colon

- higher antioxidant capacity than F/V

what does the research say on sugar and chronic disease?

- evidence doesn't support causal relationship

- strong association with excess calories (that may come from sugar) and disease

what makes SSB different than other high sugar foods?

- usually just sugar, no fibre, protein or fat

- liquids are easily absorbed

- no satiety factor

should we focus on sugar as public health message?

easy place to start, but ranked 32nd in lifestyle risk factors for mortality and disease (aka many other things to focus on)