Exam 1 Combined

Current fructose consumption estimate

About $35\text{--}73\text{ g/day}$, found in sucrose, high fructose corn syrup, fruits, and honey.

Fructose and protein glycation

Fructose is 8-10 times more reactive than glucose at glycating proteins.

Location of fructose metabolism

The liver is where fructose is mostly metabolized.

Fructokinase reaction

$$\text{Fructose} + \text{ATP} \rightarrow \text{Fructose-1-phosphate} + \text{ADP}$$

Aldolase B

Splits fructose-1-phosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde; also cleaves fructose-1,6-bisphosphate in glycolysis.

Glyceraldehyde kinase

Uses ATP to convert glyceraldehyde → glyceraldehyde-3-phosphate, feeding it into glycolysis.

Fructose entry point in glycolysis

Enters after the PFK-1 step, bypassing that regulatory checkpoint.

Tarui disease (Muscle PFK-1 deficiency)

Presents with easy fatigue, muscle weakness/stiffness with exercise, no rise in blood lactate during exercise, and symptoms improve after eating fructose.

Fructose benefit in PFK-1 deficiency

Fructose bypasses the defective PFK-1 step and can still enter glycolysis further downstream, giving muscle an alternate energy source.

Essential fructosuria

Benign condition from fructokinase deficiency; fructose is simply excreted since it's never phosphorylated.

Hereditary fructose intolerance (HFI)

Serious condition from aldolase B deficiency; fructose-1-phosphate accumulates and becomes toxic.

Consequences of fructose-1-phosphate buildup in HFI

Sequesters inorganic phosphate ($\text{P}_i$), blocking glycogen breakdown, gluconeogenesis, and oxidative phosphorylation.

Fructose/sorbitol IV infusion clinical lesson

A patient with unrecognized HFI given IV fructose/sorbitol developed severe hypoglycemia, liver failure, and died -- fructose infusions are dangerous in undiagnosed HFI.

Estimated daily galactose consumption

About $1\text{--}3\text{ g/day}$, found primarily in dairy products.

Galactitol

A sugar alcohol converted from galactose via aldose reductase (using NADPH).

Galactokinase

Phosphorylates galactose to galactose-1-phosphate using ATP.

Gal-1-P uridylyl transferase (GALT)

Converts galactose-1-phosphate + UDP-glucose into UDP-galactose + glucose-1-phosphate.

Epimerase (galactose metabolism)

Interconverts UDP-galactose and UDP-glucose.

Phosphoglucomutase (galactose pathway)

Converts glucose-1-phosphate to glucose-6-phosphate, feeding into glycolysis.

Galactose activation requirement

Further processing requires activated glucose in the form of a sugar-nucleotide (UDP-glucose).

UDP-galactose biosynthetic uses

Combines with glucose to form lactose, and is used to build glycoproteins and glycolipids.

Galactokinase deficiency

Causes minor problems, mainly cataracts, from galactitol accumulation.

GALT deficiency

Causes classic galactosemia -- a serious disease.

Epimerase deficiency (galactose pathway)

A rare cause of galactosemia.

Newborn screening for galactosemia

Legally mandated in every U.S. state.

Dietary galactose requirement

Some galactose intake is still needed to glycosylate proteins and lipids, even though UDP-galactose can come from UDP-glucose via epimerase.

Annual U.S. deaths from alcohol (CDC)

More than 140,000 deaths per year, including about 2,200 from acute alcohol poisoning.

Economic cost of alcohol in the U.S. (2010 estimate)

About $249 billion, or roughly $800 per person / $2.05 per drink.

Effects at BAC ~50 mg/dL

Warmth, flushing, loss of emotional restraint at $50\text{ mg/dL}$ BAC.

Effects at BAC ~100 mg/dL

Loss of fine motor skills, emotional instability at $100\text{ mg/dL}$ BAC.

Effects at BAC ~300 mg/dL

Stuporous but arousable; death possible at $300\text{ mg/dL}$ BAC.

Effects at BAC ~400-500 mg/dL

Comatose; death likely at $400\text{--}500\text{ mg/dL}$ BAC.

Alcohol absorption mechanism

Directly, with no receptors or transporters -- about 80% in the intestine, 20% in the stomach.

Food effect on alcohol absorption

Eating, especially fatty foods, slows gastric emptying and thus slows alcohol absorption.

Neurotransmitter effects of alcohol

Increases dopamine and serotonin release; enhances GABA (sedative) activity while glutamate (excitatory) stays elevated.

Step 1 of alcohol metabolism

Alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde, reducing $\text{NAD}^+$ to $\text{NADH}$.

Step 2 of alcohol metabolism

Aldehyde dehydrogenase 2 (ALDH2) oxidizes acetaldehyde to acetate, generating more $\text{NADH}$.

Step 3 of alcohol metabolism

Acetyl-CoA synthetase converts acetate + ATP + CoA into acetyl-CoA, AMP, and pyrophosphate.

Disulfiram (Antabuse) mechanism

Inhibits ALDH2, letting acetaldehyde accumulate and cause unpleasant symptoms after drinking.

ADH1B*2 variant

An altered ADH allele common in Asian populations that metabolizes ethanol to acetaldehyde much faster than normal.

ALDH2*2 variant

A common variant (mostly in people of Asian descent, ~560 million people) with reduced activity, causing acetaldehyde buildup, facial flushing, and increased heart rate after drinking.

MEOS (microsomal ethanol oxidizing system)

A CYP2E1-based system in the smooth ER that oxidizes ethanol using NADPH and $\text{O}_2$; induced by chronic alcohol use, can account for up to 63% of ethanol oxidation, and generates reactive oxygen species.

Chronic alcohol use and drug metabolism

Induced CYP2E1/MEOS alters metabolism of other drugs, e.g. converting acetaminophen into the toxic metabolite NAPQI.

Acetaldehyde DNA damage mechanism

Forms interstrand (and intrastrand) DNA crosslinks, contributing to its carcinogenic potential.

High NADH/NAD+ ratio effect on gluconeogenesis

Inhibits gluconeogenesis (blocks lactate$\rightarrow$pyruvate and malate$\rightarrow$oxaloacetate), which can cause lactic acidosis and hypoglycemia.

High NADH/NAD+ ratio effect on fat metabolism

Stimulates triglyceride formation and drives fatty liver disease; over 90% of AUD patients develop fatty liver.

Calories per gram of ethanol

$$7\text{ calories/gram}$$

Wernicke's encephalopathy mnemonic

CAT: Confusion, ataxia, ophthalmoplegia (treat with thiamine).

Korsakoff's psychosis mnemonic

RACK: Retrograde amnesia, anterograde amnesia, confabulation, Korsakoff's psychosis.

Cause of thiamine deficiency in alcoholics

Poor diet plus impaired thiamine absorption/utilization.

Sudden alcohol withdrawal

GABA activity falls while glutamate stays high, causing anxiety, nausea, autonomic dysfunction, and insomnia; 5-10% progress to delirium tremens, fatal in 15-20% if untreated (about 1% with benzodiazepine treatment).

Methanol metabolism danger

Metabolized by the same ADH/ALDH enzymes as ethanol, producing toxic formaldehyde/formic acid that causes eye/tissue damage and severe acidosis.

Ethylene glycol (antifreeze) metabolism

Metabolized by ADH/ALDH2 into glycoaldehyde and glycolic acid, causing severe acidosis and kidney failure.

Treatment for methanol or ethylene glycol poisoning

Saturate ADH with ethanol (the 'good' substrate) to outcompete the toxic alcohol, or give fomepizole (an ADH inhibitor).

What is the major dietary carbohydrate?

Glucose

What percent of daily glucose intake is used by the brain?

75%

How is glucose metabolized?

Glycolysis

Is glycolysis universal?

Yes

How are other carbohydrates (fructose, galactose, mannose) metabolized?

Conversion to glycolytic intermediates

Glycolysis is the conversion of glucose to what in aerobic conditions?

Pyruvate

Glycolysis is the conversion of glucose to what in anaerobic conditions?

Lactate

If glucose enters cells by facilitated diffusion, it will leave the same way, so how do you keep it there?

Phosphorylation

What enzyme catalyzes:

Glucose + ATP → Glucose-6-Phosphate + ADP

Hexokinase/glucokinase

What enzymes phosphorylate glucose?

hHexokinase and glucokinase

What term describes the set of enzymes that have different amino acid sequences but catalyze the same reaction?

Isoenzymes (Isozymes)

What is the difference between what hexokinase and glucokinase can phosphorylate?

Hexokinase: can phosphorylate other hexoses

Glucokinase: specific for glucose

Where does hexokinase vs. glucokinase work?

Hexokinase: ubiquitous

Glucokinase: restricted to liver and pancreatic β cells

Is hexokinase or glucokinase inhibited by G6P?

Hexokinases

Hexokinase is always active unless...

Unless G6P has accumulated

What helps clear glucose from the blood?

Liver glucokinase

What inhibits hexokinase?

G6P

What does glucokinase do to blood glucose in the liver?

Decreases

What does the graph of glucose concentration vs. enzyme activity look like?

Some people become diabetic even though they have pancreatic β cells that make insulin:

Type II diabetes

One class of type II occurs in people younger than usual (

Mature onset diabetes in the young (MODY)

MODY is based on a ______ mutation in one of several genes, but commonly a mutation in ___________.

Single mutation to glucokinase

How does glucokinase deficiency cause MODY?

Glucokinase activity regulates the rate of glycolysis that in turn regulates insulin secretion

Glucokinase and hexokinase are isozymes that catalyze the same reaction. Which of the following does NOT describe relevant facts about the two?

Glucokinase is found in brain and pancreatic β cells, while hexokinase is found everywhere

Red cells lack mitochondria, so they rely on __________ for ATP production.

Glycolysis

Glycolysis provides muscle the energy for ________.

Exercise

Aerobically or anaerobically, glycolysis produces energy in the form of ___.

ATP

What is the first phase of glycolysis?

Energy investment phase

The first phase of glycolysis uses _ ATP to generate what?

2 ATP → 2 phosphorylated 3-carbon intermediates (G3P)

What happens to GAP (Glyceraldehyde-3-Phosphate)?

Oxidized and phosphorylated by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to form 1,3-bisphosphoglycerate

Glyceraldehyde 3P dehydrogenase shows ________ cooperativity.

Negative cooperativity

What is NAD+?

Nicotinamide adenine dinucleotide - a coenzyme from Vitamin B3 that functions as an electron carrier

NAD+ reversibly accepts _e- and _H+ from substrate

2e- and 1H+

What is niacin?

Vitamin B3

What happens when you have a niacin deficiency?

Diarrhea, dermatitis, dementia

What happens when you run out of NAD+ (i.e. under anaerobic conditions)?

Lactate dehydrogenase (LDH) regenerates oxidized NAD+

Important glycolysis metabolites

• Glycogen, ribose, NADPH

• Glucosamine

• Triglycerides, phospholipids

• NADH

• 2,3-bisphosphoglycerate (RBCS)

• Serine

• Alanine, lactate

T/F: The regulation of glycolysis occurs at steps that are close to equilibrium.

False; far from equilibrium

What does a defect in glucokinase cause?

MODY

What does a defect in pyruvate kinase cause?

Warburg Effect

What regulates hexokinase?

Inhibited by glucose-6-phosphate

What regulates phosphofructokinase I?

Inhibited by ATP

Promoted by AMP

What regulates pyruvate kinase?

Promoted by fructose,1,6,BP

What does PFK-1 do?

Converts fructose-6-P to F1,6P2

What is the key regulated step in glycolysis?

PFK-1

What is a strong inhibitor of PFK-1?

Intracellular ATP