BCH210H1 Lecture Notes - Lecture 35: Ketogenic Amino Acid, Acetyl-Coa, Citric Acid Cycle

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amethystfly536

25 May 2018

School

UTSG

Department

Biochemical Engineering and Applied Chemistry

Course

BCH210H1

Professor

Stavroula Andreopoulos

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Lecture 35: Ketogenesis and Diabetes

Recall B-oxidation

• Fat reseres are a huge soure of Aetyl CoA ad geerate ore ATP ia β-oxidation than glucose alone

- Acyl CoA is dependant on oxaloacetate → need to do something else if not enough

• Catabolism of ketogenic amino acids can also produce Acetyl CoA (Atkins diet?)

- Atkins diet – high protein, low carb diet → lots of acetyl CoA but not enough oxaloacetate from glucose

• Fat and amino acid catabolism occurs when epinephrine and glucagon (GPCR signalling) dominate (activation of

certain enzymes)

• Acetyl CoA enters the Citric Acid Cycle but is limited by the amount of oxaloacetate present

• Ketogenesis occurs when acetyl CoA levels rise so that ketone bodies can be used as an alternate fuel source to

glucose

- Ketones can be used throughout the body after being released into the blood

- Amino acids → acetyl CoA → ketone bodies

Fates of acetyl CoA

• We need oxaloacetate to make citrate (generate energy through NADH,etc) where the energy created can go

back to inhibit CAC, causing citrate build up

- Citrate will be exported out of mitochondria for fat synthesis or can synthesize cholesterol

- Need to have oxaloacetate for this

• No oxaloacetate (aka no pyruvate carboxylase) then ketones made – can use to generate ATP in the liver

• Acetyl CoA → Citrate → Citric acid cycle → CO2 + energy

Amino acids and carbon metabolism

• We do’t at to reak aio aids or aro

but if we must we need to – proteases break

them into individual AAs

• AA can be used in liver to make ketone bodies

(ketogenic AA) or glucose (glucogenic AA)

• CAC will go all the way around oxaloacetate to

generate glucose via GNG

Ketone bodies produced in the liber

• Only two have ketone groups –

betahydroxybutyrate has carboxyl acid

• Structures resemble acetyl CoA – first two used as energy source but

contribute to acidosis

- Acetone is exhaled waste produce – can detect ketogenesis via this

• Because pKa of COO- group, proton will be released, creating acidosis

• At physiological pH, it is deprotonated and will contribute to acidosis

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Ketone body synthesis

• Made in the mitochondrial matrix in the liver –

3 acetyl CoA will come together to form 3

ketone bodies

1. Condensation reaction to bring together two

acetyl CoA molecules

2. HMB-CoA synthase will use another CoA – this

is made in the cholesterol synthesis

- Creates molecule HMG-CoA

3. Acetoacetate made from HMG-CoA lyase – first

ketone body

- Lost CoA molecule so it can be exported and used for energy in other cells

4. Dehydrogenase will metabolize further to create 3-hydroxy-butrate using NADH (optional)

- Reaction occurs because this molecule is more stable

- You can also decarboxylate it to create acetone (happens spontaneously)

• Pathway only makes one at a time, but it happens a lot causing the pool of ketones

• Oxaloacetate levels low when you have low carbohydrate concentrations

• Fored i lier itohodria usig aetyl CoA fro β-oxidation (& amino acid degradation)

• Ketone bodies leave the liver and enter the blood

• Aetoaetate ad β-hydroxybutyrate can be used as fuel by the brain, heart, muscle and kidney cells

• The production of acidic ketone bodies contributes to a drop in blood pH (acidosis)

• Acetone is a waste product and gives a characteristic fruity breath symptom

• Conversion back to Acetyl CoA can provide access to large amounts of ATP

Use of ketone bodies as fuel by brain or other tissues

• Reverse reaction to create 2 acetyl CoA via reaction beside – used to create energy

Blood pH, CO2 and bicarbonate

• H+ + HCO3- → H2CO3 → H2O + CO2

• CO2 decrease from exhaling deeply, [HCO2-] decreases

• Therer’s a uffer syste to help itigate the protoatio

- Bicarbonate combines with protons to break down into H2O and CO2

- CO2 exhaled to help buffer and remove protons from blood

• High exhale might be an indicator of acidosis, but consequence is that bicarbonate is

reduced – too much is problem because if you get rid of all bicarbonate, it will worsen

Keto(acido)sis

• Occurs when ketone levels rise in the body due to depleted liver glycogen stores

• Blood buffering system initially compensates along with H+ absorption by bone and tissue and renal secretion

• Acidosis occurs when blood pH drops below 7.35 (why is this bad?)

- Would cause dissociation of proteins that will get protonated → enzymatic sites

- Would cause denaturation of proteins that would be detrimental

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BCH210H1 Full Course Notes

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Based on âMorgan: A case of Diabetesâ by Lisa Rubin and Clyde Freeman Herreid (National Center for Case Study Teaching in Science)

The Patient:

Morgan Water is a 27-year old Native American that lives on a reservation in Oklahoma. Nearly Â¼ of Morganâs tribe has diabetes but she has no direct family history of diabetes, heart disease, or other serious conditions. She is however obese (BMI = 32) and leads a sedentary lifestyle. Morgan has been suffering from an increasing persistence of symptoms including unusual thirst, dizziness, blurred vision, and numbness in her right foot. The symptoms have been developing over several months but as she is planning her wedding she attributed them to nerves. She is finally persuaded to see her family doctor. Her non-fasting blood glucose level was elevated so the doctor has her return the next morning for a fasting blood sample so they could more accurately measure her blood glucose and insulin. Her blood results are below:

Test	Morganâs values	Normal range	Pre-Diabetic range	Diabetic range
Plasma glucose, mg/dl	260	70 -139	140 - 199	â¥ 200
Fasting glucose, mg/dl	140	â¤ 99	100 - 125	â¥ 126
A1C, %	7.6	~ 5	5.7 â 6.4	â¥ 6.5
Fasting Insulin, mIU/ml	34	2 - 10	10 - 20	â¥ 20

The recommendation of Morganâs doctor was to improve her exercise, good nutrition, and weight loss. He recommends meeting with a nutritionist to assist Morgan in her weight loss goals. When Morgan got home and told her family the diagnosis they however had LOTS of suggestions on how she can lose weight. Below is a description of the advice given to her by three family members.

Best friend Savannah:

âYou know how Iâve been losing weight? Well, Iâve been on the Atkinsâ Diet. I heard about it on TV. Itâs great! You get to eat steak, chicken wings, and all the good stuff. All you have to do is limit carbohydrate intake. You should definitely give it a try. This diet has been around for years and it has worked for lots of people, including me.â

*Note: Atkinâs Diet recommends: 10% carbohydrates, 55% fats, 35% protein

Brother Alan:

âI think the best thing for you to do is exercise and stop eating all of that pizza and candy and food filled with fat. Our people never used to eat that junk. I say eat meals that are nutritionally balanced and high in fiber and low in refined sugars and saturated fats. And run a lot. Stop sitting around the house.â

Grandfather:

âMorgan, it is true that it is best to live in harmony and balance â to eat a nutritionally balanced diet that includes carbohydrates, proteins, and âgoodâ fats to meet your bodyâs needs. That is good. But look to your heritage. Our people were never overweight before we started eating âcivilizedâ food. Look to our native diet. I think you should look to traditional herbal remedies for help. What Alan says is true. Exercise is good. But it is sometimes not enough. Our people have always looked to natural medicine for cures. They will lift your spirits and energize you. Then you will lose weight and you will be healthy again. I hear the herbs from the diet shop are safe and good. But you must take them like the medicine label says. It canât hurt to try them.â

*Note: these herbal supplements Morganâs grandfather is recommending contain the herb

ephedra (ephedrine).

Question 5:

Given Morganâs metabolic state, what is the primary fuel source for her cells currently?

A. Carbohydrates (glucose)

B. Fats

C. Proteins

D. It is a balance of all three

Question 6:

Metabolic ketoacidosis is a common problem with diabetics, which is caused by which of the following?

A. Excessive oxidation of fatty acids, leading to an accumulation of ketone bodies in the blood.

B. Excessive oxidation of glucose, leading to an accumulation of ketone bodies in the blood.

C. Excessive oxidation of proteins, leading to an accumulation of ammonia in the blood.

D. Hyperglycemia.

Question 7:

Which weight loss suggestion is designed to achieve some level of ketosis?

A. Atkins Diet

B. Exercise

C. High fiber diet

D. Herbal treatments

Question 8:

One major side effect of the herbal supplement can be hot flashes and increased perspiration due to increased thermogenesis, what is the likely cause of the heat production?

A. Increasing the activity of phosphfructokinase-1.

B. Increasing the activity of the pyruvate dehydrogenase complex.

C. Increasing the activity of citrate synthase.

D. Increasing the activity of uncoupling proteins.

Question 9:

Would substituting fiber and complex carbohydrates (larger % cellulose) for the simple sugars and starches (high sucrose and amylose/amylopectin) help Morgan lose weight, why?

A. Yes, because complex carbohydrates like cellulose are largely indigestible so they pass through

the digestive tract without being absorbed.

B. Yes, cellulose contains less glucose residues than amylose or amylopectin.

C. Yes, because the fructose in sucrose is much more responsible for weight gain than the glucose.

D. No, because cellulose, amylose, and amylopectin are all composed of glucose so it doesnât

matter.

Question 10:

Which weight loss suggestion will lead to an increased need for gluconeogenesis?

A. Atkins Diet

B. Exercise

C. High fiber diet

D. Herbal treatments

BCH210H1 Lecture Notes - Lecture 35: Ketogenic Amino Acid, Acetyl-Coa, Citric Acid Cycle

BCH210H1 Full Course Notes

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