Galactose, Fructose, and Alcohol Metabolism (Video Notes)

Vocabulary flashcards covering key terms from galactose, fructose, and alcohol metabolism in the lecture notes.

Galactose Metabolism Overview

The biochemical pathway responsible for converting dietary galactose, primarily derived from lactose, into glucose-1-phosphate (G-1-P) or UDP-galactose. These products can then enter glycolysis for energy or be used in glycogen synthesis and glycoconjugate formation. Key enzymes involved are Galactokinase (GALK), Galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose 4-epimerase (GALE).

Key Regulated Enzymes in Galactose Metabolism

• Galactokinase (GALK): Phosphorylates galactose to galactose-1-phosphate (Gal-1-P).
• Galactose-1-phosphate uridyltransferase (GALT): Converts Gal-1-P and UDP-glucose to UDP-galactose and glucose-1-phosphate (G-1-P).
• UDP-galactose 4-epimerase (GALE): Interconverts UDP-galactose and UDP-glucose.

Role of Galactokinase (GALK)

GALK is the first enzyme in galactose metabolism, responsible for phosphorylating incoming galactose into galactose-1-phosphate (Gal-1-P), trapping it within the cell for further metabolism. This step requires ATP.

Consequences of Galactokinase (GALK) Deficiency

An autosomal recessive disorder where the lack of GALK leads to the accumulation of galactose in the blood (galactosemia) and urine (galactosuria). Excess galactose is then shunted by aldose reductase to galactitol, which accumulates in the lens of the eye, causing infantile cataracts. These cataracts are typically the most prominent symptom, and liver and kidney involvement is usually mild or absent.

Role of Galactose-1-phosphate uridyltransferase (GALT)

GALT is a crucial enzyme in the Leloir pathway, catalyzing the transfer of a uridine monophosphate (UMP) group from UDP-glucose to galactose-1-phosphate (Gal-1-P), producing UDP-galactose and glucose-1-phosphate (G-1-P). This reaction is essential for converting galactose into a usable form for energy and biosynthesis.

Consequences of GALT Deficiency (Classic Galactosemia)

This severe autosomal recessive disorder, known as Classic Galactosemia, results from a deficiency in GALT. It leads to a catastrophic accumulation of galactose-1-phosphate (Gal-1-P) and galactose. The accumulation of these toxic intermediates causes:

1. Liver damage: Jaundice, hepatomegaly, and cirrhosis.
2. Brain damage: Intellectual disability and developmental delays.
3. Cataracts: Due to galactitol accumulation in the lens, similar to GALK deficiency but often more severe if untreated.
4. Kidney damage: Renal tubular dysfunction.
5. Neonatal sepsis (E. coli): Increased susceptibility.

How Galactosemia Affects Liver and Brain Tissues

In Classic Galactosemia (GALT deficiency), the buildup of toxic galactose-1-phosphate (Gal-1-P) and galactose in cells directly damages the liver and brain. In the liver, it impairs metabolic processes, leading to jaundice, hepatomegaly, and can progress to cirrhosis. In the brain, it interferes with neurotransmitter synthesis and myelin formation, resulting in intellectual disability, developmental delays, and neurological dysfunction if not managed with a strict galactose-free diet.

Role of UDP-galactose (UDP-Gal)

UDP-galactose serves as an activated galactose donor molecule. It is crucial for the synthesis of various glycoconjugates, including glycoproteins, glycolipids, and mucopolysaccharides, which are essential components of cell membranes and extracellular matrix. It's also interconverted with UDP-glucose by GALE.

UDP-glucose

UDP-glucose is a nucleotide sugar donor that plays a vital role in carbohydrate metabolism. It serves as a substrate for GALT, reacting with galactose-1-phosphate to form UDP-galactose and glucose-1-phosphate. It is also involved in glycogen synthesis and other metabolic pathways.

Galactose Metabolism and Cataract Formation

Cataracts, a clouding of the eye lens, can form in both GALK and GALT deficiencies. When galactose accumulates, the enzyme aldose reductase reduces it to a sugar alcohol called galactitol. Galactitol is osmotically active and cannot freely exit the lens, leading to osmotic stress and swelling of lens fibers, ultimately causing opacification (cataract formation).

Aldose Reductase

An enzyme that reduces aldoses (sugars with an aldehyde group), such as galactose and glucose, into their corresponding sugar alcohols (galactitol from galactose, sorbitol from glucose). Its activity is particularly problematic in conditions with high sugar levels, contributing to osmotic damage in tissues like the eye lens, nerves, and kidneys.

Galactitol

A sugar alcohol formed from the reduction of galactose by aldose reductase. Its accumulation in the lens of the eye in galactosemic conditions creates an osmotic gradient, drawing water into the lens and leading to swelling and characteristic cataract formation.

Lactose Metabolism

Lactose, a disaccharide found in milk, is hydrolyzed into glucose and galactose in the small intestine. This process is primarily catalyzed by the enzyme lactase.

Lactase

A brush-border enzyme located in the small intestine that specifically hydrolyzes the disaccharide lactose into its constituent monosaccharides: glucose and galactose. This enzymatic breakdown is essential for the absorption of dairy sugars.

Symptoms of Lactose Intolerance

Lactose intolerance is caused by a deficiency of lactase, leading to incomplete digestion of lactose. Undigested lactose passes into the large intestine, where it is fermented by gut bacteria, producing gas and short-chain fatty acids. This results in symptoms such as abdominal bloating, cramps, flatulence, and osmotic diarrhea after consuming lactose-containing foods.

Fructose Metabolism Overview

Fructose is primarily metabolized in the liver. It bypasses the phosphofructokinase-1 (PFK-1) regulatory step of glycolysis, leading to its rapid conversion into glycolytic intermediates like dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate. The key initial enzymes are fructokinase and aldolase B.

Key Regulated Enzymes in Fructose Metabolism

• Fructokinase: Phosphorylates fructose to fructose-1-phosphate (F-1-P).
• Aldolase B: Cleaves F-1-P into dihydroxyacetone phosphate (DHAP) and glyceraldehyde.
• Hexokinase: Can phosphorylate fructose to fructose-6-phosphate (F-6-P) but only at high fructose concentrations, and it has a lower affinity for fructose than glucose.

Role of Fructokinase

Fructokinase is found predominantly in the liver, kidney, and small intestine. It phosphorylates dietary fructose at the C-1 position to form fructose-1-phosphate (F-1-P), a reaction that traps fructose within these cells and commits it to hepatic metabolism. This step is ATP-dependent.

Essential Fructosuria

A benign, autosomal recessive metabolic disorder caused by a deficiency of fructokinase. Individuals with essential fructosuria cannot phosphorylate fructose effectively, leading to its accumulation in the blood and excretion in the urine (fructosuria). It is generally asymptomatic and harmless, requiring no specific treatment, as fructose can still be slowly metabolized by hexokinase in other tissues.

Role of Aldolase B

Aldolase B (or fructose-1-phosphate aldolase) is the enzyme responsible for cleaving fructose-1-phosphate (F-1-P) into two 3-carbon products: dihydroxyacetone phosphate (DHAP) and glyceraldehyde. These products can then directly enter the glycolytic pathway. Aldolase B is primarily active in the liver.

Consequences of Aldolase B Deficiency (Hereditary Fructose Intolerance)

Also known as Hereditary Fructose Intolerance (HFI), this is a serious autosomal recessive condition. A defective Aldolase B enzyme leads to the accumulation of fructose-1-phosphate (F-1-P) in the liver, kidney, and small intestine. This accumulation has several severe consequences after fructose or sucrose intake:

1. Hypoglycemia: F-1-P traps intracellular inorganic phosphate (P_i), depleting ATP and inhibiting glycogenolysis (breakdown of glycogen) and gluconeogenesis (synthesis of new glucose).
2. Liver damage: Jaundice, vomiting, hepatomegaly, and potentially liver failure due to F-1-P toxicity.
3. Kidney damage: Renal tubular dysfunction.
   Treatment involves strict avoidance of all fructose and sucrose in the diet.

Fructose-1-phosphate (F1P)

The metabolic intermediate formed when fructokinase phosphorylates fructose. In hereditary fructose intolerance (HFI) due to Aldolase B deficiency, F-1-P accumulates to toxic levels within cells. This accumulation sequesters inorganic phosphate (P_i), leading to ATP depletion and inhibition of crucial pathways like glycogenolysis and gluconeogenesis.

Alcohol Metabolism Overview

Ethanol is primarily metabolized in the liver through two main enzyme systems: the Alcohol Dehydrogenase (ADH) pathway (cytosolic) and the Microsomal Ethanol Oxidizing System (MEOS) (ER). Both pathways involve the oxidation of ethanol to acetaldehyde, and then acetaldehyde to acetate, generating significant amounts of NADH.

Key Regulated Enzymes in Alcohol Metabolism

• Alcohol Dehydrogenase (ADH): Oxidizes ethanol to acetaldehyde, reducing NAD^+ to NADH. Primarily active at low to moderate alcohol intake.
• Aldehyde Dehydrogenase (ALDH): Oxidizes acetaldehyde to acetate, reducing NAD^+ to NADH. Present in mitochondria and cytosol.
• Cytochrome P450 (CYP2E1) (part of MEOS): Oxidizes ethanol to acetaldehyde, consuming NADPH. Induced at high alcohol intake, and produces reactive oxygen species.

Role of Alcohol Dehydrogenase (ADH)

ADH is the primary enzyme responsible for the first step of ethanol metabolism, mainly occurring in the cytoplasm of liver cells. It oxidizes ethanol to acetaldehyde, while simultaneously reducing NAD^+ to NADH. This reaction is the major contributor to the increased NADH/NAD^+ ratio seen during alcohol consumption.

Role of Aldehyde Dehydrogenase (ALDH)

ALDH is a key enzyme in the detoxification of alcohol. It rapidly oxidizes the highly toxic intermediate acetaldehyde into acetate. This reaction also generates NADH from NAD^+. Genetic variations in ALDH, particularly a less active variant, can lead to acetaldehyde accumulation and unpleasant flushing symptoms after alcohol consumption.

Acetaldehyde

A highly toxic intermediate produced during ethanol metabolism. Acetaldehyde is responsible for many of the unpleasant physiological effects associated with alcohol consumption, including flushing, nausea, vomiting, headaches, and palpitations. It also forms protein adducts, disrupting cellular function, contributing to liver damage, and increasing cancer risk.

Acetate

The final major non-toxic product of alcohol metabolism, formed by the oxidation of acetaldehyde by ALDH. Acetate is released from the liver into the blood and can be converted to acetyl-CoA in various tissues (including the liver, but often extrahepatically) for use in the TCA cycle for energy production or fatty acid synthesis.

Disulfiram

A drug used in the treatment of chronic alcoholism. Disulfiram inhibits aldehyde dehydrogenase (ALDH), leading to a buildup of toxic acetaldehyde after alcohol ingestion. This causes highly unpleasant symptoms (flushing, nausea, vomiting, dizziness) that deter individuals from consuming alcohol.

NADH Production in Alcohol Metabolism

Both steps of ethanol oxidation—from ethanol to acetaldehyde (via ADH) and from acetaldehyde to acetate (via ALDH)—generate NADH from NAD^+. This significantly increases the NADH/NAD^+ ratio in the liver, which has profound effects on other metabolic pathways.

Impact of Alcohol on Gluconeogenesis and Glycolysis

The elevated NADH/NAD^+ ratio from alcohol metabolism has several key effects on carbohydrate metabolism:

1. Inhibition of Gluconeogenesis: High NADH shifts metabolic intermediates away from glucose synthesis. Pyruvate is converted to lactate, and oxaloacetate is converted to malate, effectively stopping gluconeogenesis and potentially leading to hypoglycemia in fasting or malnourished individuals.
2. Altered Glycolysis: While direct inhibition of glycolysis isn't the primary effect, the high NADH pushes the equilibrium of reactions like lactate dehydrogenase and malate dehydrogenase, influencing the pools of glycolytic intermediates. Over time, increased fatty acid synthesis from excess NADH also impacts glucose utilization.

Effects of High NADH/NAD+ Ratio (Alcohol Metabolism)

A dramatically elevated NADH/NAD^+ ratio due to alcohol metabolism leads to several metabolic derangements:

• Lactic acidosis: Pyruvate is converted to lactate (to regenerate NAD^+), causing blood acidosis.
• Hypoglycemia: Due to inhibition of gluconeogenesis.
• Fatty liver (hepatic steatosis): Increased fatty acid synthesis and decreased fatty acid oxidation due to high NADH. Glycerol-3-phosphate synthesis is favored, providing backbone for triacylglycerol synthesis.
• Ketoacidosis: If prolonged fasting, acetyl-CoA from fatty acid oxidation (impaired TCA due to high NADH) can be shunted to ketone body production.

Ketogenesis (Alcohol-induced)

The increased NADH/NAD^+ ratio from alcohol metabolism inhibits the TCA cycle, causing acetyl-CoA to accumulate. Additionally, in prolonged fasting ( common with chronic alcohol use), increased fatty acid mobilization and oxidation further contribute to acetyl-CoA production. This excess acetyl-CoA is then shunted towards the synthesis of ketone bodies, leading to alcoholic ketoacidosis when combined with hypoglycemia.

Hypoglycemia (Alcoholic)

A dangerous drop in blood glucose levels that can occur during or after heavy alcohol consumption, especially in individuals who are fasting or malnourished. It is primarily caused by the inhibition of hepatic gluconeogenesis due to the high NADH/NAD^+ ratio generated during ethanol metabolism, which depletes essential substrates needed for glucose synthesis.