CFB 23: Other Sugars/Alcohol (Biochemistry)

Why does fructose help those who are easily fatigued?

Bypass defect in Muscle PFK I

Essential fructosuria

Fructokinase deficiency

Why is fructose-1-phosphate toxic if built up?

Sequesters Pi
Blocks glycogen breakdown, glucose synthesis, and oxidative phosphorylation (makes you run out of energy)

What is hereditary fructose intolerance a defect in?

Aldolase B

What does Aldolase B do?

Splits fructose-1-phosphate into DHAP 3P and glyceraldehyde

Why would eating too much candy make you sick?

Accumulation of fructose-1-phosphate

A child ate fruit and felt sick and jaundiced after a few days. Lab tests showed a marked elevation in blood fructose, hypoglycemia, and lactic acidosis. The most likely explanation for the acidosis is:

Phosphate depletion blocking glycolysis, oxidative phosphorylation and gluconeogenesis

What does the Polyol Pathway connect?

Glucose and fructose via sorbitol

What are conversions of particular interest in the Polyol (Sorbitol-Aldose Reductase) Pathway?

In seminal vesicles (fuel for sperm) and in the eye (retinopathy in diabetes)

Further galactose metabolism requires what?

Activated sugar in the form of a sugar-nucleotide

Activated _______ is used to activate galactose.

Glucose

Other fates of galactose

Galactitol
Lactose
Glycoprotein/lipid

Metabolic diseases of galactose

Galactokinase deficiency
Classic Galactosemia

Galactokinase Deficiency

Galactitol accumulates in blood & urine
Infantile cataracts (no developmental delay)

Classic Galactosemia

Gal-1-P-uridylyl transferase issues

An infant recovering from febrile gastroenteritis has abdominal distension after feeding. A deficiency of which enzyme causes the problem?

Lactase

An infant presents with vomiting, jaundice, and hepatomegaly. There is a failure to thrive and developmental delay. A deficiency of which enzyme most likely causes the problem?

Galactose-1-phosphate uridylyltransferase (GALT)

What does GALT catalyze the conversion of?

Galactose-1-P to UDP-galactose

T/F: Alcohol needs a receptor/transporter.

False; alcohol is absorbed directly

Factors that influence BAC curves

How many drinks
BMI
Gender
Co-consumption of other substances

Is ethanol soluble in fat?

Not very

Alcohol enhances release of ________ and _________.

Dopamine and serotonin

What acts like a sedative to calm the brain, and what excites the brain and makes it more active?

GABA: sedative
Glutamate: excites

What percent of alcohol absorption is intestinal vs. stomach?

80% intestinal
20% stomach

Eating what type of food slows gastric transport (and hence absorption)?

Fatty foods

What is the first step in alcohol metabolism?

Oxidation of ethanol to acetaldehyde

What is the most important route of clearance in alcohol metabolism?

Alcohol metabolism by dehydrogenase in liver

To oxidize ethanol to acetaldehyde, ____ is reduced to ____.

NAD+ reduced to NADH

How many ADHs are there?

At least 7

What is the major ADH?

ADH1B*1

What is ADH1B*2?

An altered allele very common in Asian populations

What does ADH1B*2 do?

Higher substrate affinity so alcohol is metabolized much more quickly

What is the microsomal ethanol oxidizing system?

Chain of enzymes that oxidize alcohol to break it down. Handles about 10% of alcohol where the remaining 10% after ADH is excreted in breath and urine

What induces MEOS?

Chronic alcohol consumption

What does MEOS generate?

Reactive oxygen (ROS)

What affects the metabolism of drugs?

MEOS

Induction of MEOS increases/decreases alcohol clearance?

Increases

Acetaldehyde induces ___ damage.

DNA

What cancers are associated with alcohol?

Mouth, throat, larynx
Esophagus
Colon + rectum
Liver
Breast

What is the second step in alcohol metabolism?

Oxidation of acetaldehyde to acetic acid

What catalyzes the oxidation of acetaldehyde to acetic acid?

Aldehyde dehydrogenase 2

What is the ALDH2*2 variant?

Reduces activity
Facial flushing, increased heart rate after alcohol

What is the third step of alcohol metabolism?

Conversion of some acetate to acetyl-CoA

What catalyzes the conversion of acetate to acetyl-CoA?

AcetylCoA Synthetase

High NADH/NAD+ ratio created by ethanol metabolism has what consequence?

Inhibits gluconeogenesis by reducing oxaloacetate

Production of NADH stimulates ____________ formation.

Triglyceride

What is the result of NADH stimulating triglyceride formation?

>90% of AUD sufferers have fatty liver disease

What vitamin are alcoholics often deficient in?

Thiamine

Symptoms of Wernicke's Encephalopathy

Confusion
Ophthalmoplegia
Ataxia
Thiamine Tx

Symptoms of Korsakoff's Psychosis

Retrograde amnesia
Anterograde amnesia
Confabulation
Korsakoff's psychosis

Toxic ethanol relatives

Methanol
Glycols such as antifreeze

T/F: Metabolism of methanol and glycols uses the same enzymes as ethanol.

True

What are problems with methanol metabolism?

Tissue damage (eye), acidosis

What is ethanol metabolized to?

Acetaldehyde

What metabolizes ethanol?

ADH, CYP2E1 (MEOS), or catalase

What is the major route of clearance?

Liver ADH

In chronic alcohol users, the ____ system can be the major metabolic route.

MEOS

Acetaldehyde is converted to acetate by _____.

ALDH2

High activity ___ and low activity _____ is common in asian populations.

High ADH, low ALDH2

Because NADH is generated by ADH and ALDH2, an increased NADH/NAD+ ratio inhibits what? and supports what?

Inhibits gluconeogenesis, supports triglyceride formation

What is acetate converted to?

Acetyl CoA

T/F: Relatives of ethanol (methanol, glycols) are toxic.

True

An infant is found to be developing cataracts, but otherwise is relatively normal. Galactose is elevated in the blood and urine. A galactokinase deficiency is diagnosed. Which enzyme reaction is catalyzed by galactokinase?

Galactose --> galactose-1-P

Under normal circumstances in ordinary people, which coenzyme is used to metabolize ethanol to acetaldehyde?

NAD+

Two infants present with difficulties in fructose metabolism. The first one is defective in fructokinase, while the second is defective in aldolase B. What problem makes you more concerned about the infant with the aldolase B defect?

Loss of free phosphate

Alcoholism is found less commonly in Asian populations than in western populations. This is because:

Asians often have isozymes of alcohol dehydrogenase that result in quicker loss of blood alcohol and longer persistence of acetaldehyde

An individual who has consumed a large amount of alcohol is brought to the emergency room in hypoglycemic shock. The hypoglycemia most likely comes from an elevated ratio of:

NADH/NAD+

A high liver NADH/NAD indicates...

The person has been consuming alcohol

Alcohol increases the risk of cancer. Which of the following mechanisms is most likely the most important:

Acetaldehyde modification of DNA

Which of the following statements about alcohol dehydrogenase is correct?

The high activity isoform ADH is common in Asian populations