8. Uronic acid pathway of glucose and other hexoses/glucuronic acid pathway

Define the glucuronic acid pathway.

• An alternative oxidative pathway for glucose

• Deals with the synthesis of glucuronic acid, pentoses, and vitamins

Does glucuronic acid pathway lead to the generation of ATP?

No

Where does the glucuronic acid pathway take place?

Cytoplasm of liver cells

What is the first step of glucuronic acid pathway?

• Glucose is isomerized to glucose-6-phosphate and then glucose-1-phosphate

• Enzymes used are hexokinase and phosphoglucomutase, respectively

What is the second step of the glucuronic acid pathway?

• Glucose-1-phosphate reacts with UTP to form uridine diphosphate glucose (UDPGlc)

• Enzyme used is UDPGlc pyrophosphorylase

What is the third step of the glucuronic acid pathway?

• UDPGlc is oxidized at carbon 6 to yield UDP-glucuronate/UDP-Glucuronic acid

• Enzyme used is NAD-dependent UDPGlc dehydrogenase

UDP glucuronic acid is the ______ form of glucuronic acid.

active

What is the importance of glucuronic acid pathway?

Provides UDP Glucuronic acid, which is used for:

1. Conjugation of less polar compounds etc bilirubin, steroids and some drugs, making them more water soluble (detoxicated)

2. Synthesis of glycosaminoglycans (mucopolysaccharides) e.g. heparin and hyaluronic acid

3. Precursor of L-ascorbic acid in some plants and animals

What are the effects of drugs on the uronic acid pathway?

• Barbiturates, antipyrine, and aminopyrine will increase uronic acid pathway

• Leads to availability of more glucuronate for conjugation

Why can’t ascorbic acid be synthesized in humans, primates, guinea pigs, and bats?

Due to absence of L-gulunolactone oxidase

(So, Vitamin C essential in diet)

Describe essential pentosuria.

• Inborn error of metabolism

• 1 in 2,500 births

• In pathway, L-xylulose is converted to D-xylitol by NADP-dependent enzyme xylulose reductase

• Deficiency in enzyme leads to L-xylulose excreted in urine, leads to pentosuria

• Detected by Benedict’s test

• Not harmful condition

• Differentiated from diabetes mellitus by HbA1c, fasting blood sugar test for DM

Describe the polyol pathway of glucose/sorbitol pathway.

• Directly related to glucose conc. and higher in uncontrolled DM

• AKA sorbitol-aldose reductase pathway

• Polyol pathway appears to be involved in diabetic complications, esp. microvascular damage to retina, kidney, and nerves

• Sorbitol poorly absorbed from intestine, cannot cross cell membranes, cannot diffuse out of cells easily and gets trapped in them

• When accumulates produces osmotic stress on cells by drawing water into insulin-dependent tissues

What are the reactions of polyol pathway/sorbitol pathway?

1. Glucose reduced to sorbitol using aldose reductase

2. Sorbitol oxidized into fructose using sorbitol dehydrogenase

Where is sorbitol present normally?

Lens of eyes

In DM, glucose level increases, which increases sorbitol content. What does this lead to?

Osmotic damage of tissues and developement of cataracts

How does sorbitol pathway play a role in diabetic renal complications?

Aldose reductase metabolizes excess glucose to toxic metabolites which induce hyperfiltration and glomerular dysfunction

Sorbitol pathway produces fructose which is present in a large quantity in _____ and also found in ___.

semen

CSF (cerebrospinal fluid)

Where is the polyol pathway active?

Brain

Where is the polyol pathway inactive?

Liver

_______ is found in corn syrups and honey in high concentrations.

Fructose

Entry of fructose into cells is not _______-_________.

insulin-dependent

Fructose does not promote the secretion of _______.

insulin

Fructose is metabolized by the ______.

liver

The pathway of ___________ of fructose differs in ______ and ______.

utilization

muscle

liver

What is the first step in fructose metabolism?

• Fructose phosphorylated into fructose-1-phosphate

• Enzyme used is fructokinase

• ATP converted into ADP

What is the second step in fructose metabolism?

• Fructose-1-phosphate split into glyceraldehyde and DHAP (dihydroxyacetone phosphate)

• Enzyme used is fructose-1-phosphate aldolase

What happens to glyceraldehyde?

• Glyceraldehyde phosphorylated to glyceraldehyde-3-phosphate

• Enzyme used is triose kinase

• ATP is converted into ADP

What happens to DHAP?

• DHAP converted into glyceraldehyde-3-phosphate

• Enzyme used is TIM (triphosphate isomerase)

Muscles that contain only __________ can phosphorylate fructose into ___ which is a direct glycolytic ____________.

hexokinase

F6P

intermediate

Why is fructose metabolism in the muscle not a significant pathway for fructose metabolism?

Hexokinase has a very low affinity to fructose compared to glucose unless it is present at high conc. in the blood

Free fructose is seen in large amounts in _______ ______.

seminal plasma

Fructose is secreted by _______ ________.

seminal vesicles

Fructose provides energy for mobility of ___________.

spermatozoa

What is seen in people who have blocked seminal ducts?

Azoospermia

Deficiency of fructose correlates with

male infertility

What are 2 hereditary defects of fructose metabolism?

1. Fructosuria

2. Hereditary Fructose Intolerance (HFI)

Describe fructosuria.

• Benign metabolic defect

• Caused by deficiency in fructokinase

• Excess accumulated fructose lost in urine

• Urine gives positive benedicts and seliwanoff’s test

• 1 in 130,000 births

Describe Hereditary Fructose Intolerance (HFI).

• Autosomal recessive inborn error of metabolism

• 1 in 20,000 births

• Caused by deficiency in aldolase B

• Leads to accumulation of F1P

• Seen when sucrose introduced into diet of infant usually 6 months of age

• Accumulation of F1P inhibits glycogen phosphorylase, leading to accumulation of glycogen in liver and associated with hypoglycemia

What are the symptoms and treatment of HIF.

• Vomiting

• Loss of appetite

• Infants fail to thrive

• Hepatomegaly and jaundice

• Death, if damage of liver progresses

• Treatment is to withdraw fructose from diet

• Will immediately relieve symptoms

What is the major source of galactose?

Dairy products

How does galactose enter glycolysis?

By its conversion to glucose-1-phosphate which occurs through series of steps

Where is galactose metabolized?

Liver

What test is done to asses functional capacity of liver?

Galactose tolerance test

What is the first step of galactose metabolism?

• Galactose is phosphorylated into galactose-1-phosphate

• Enzyme used is galactokinase

• ATP is converted into ADP

What is the second step of galactose metabolism?

• Galactose-1-phosphate is converted into glucose-1-phosphate

• Enzyme used is Galactose-1-phosphate uridylyltransferase

• Cofactor is UDP glucose

Where does the UDP glucose come from?

• Glucose-1-phosphate is converted into UDP glucose

• Enzyme used is UDP-glucose pyrophosphorylase

• UDP-glucose is converted into UDP-galactose

• UDP-galactose is converted back to UDP-glucose using UDP-galactose epimerase

• UDP-glucose used as cofactor again

What is the third step of galactose metabolism?

• Glucose-1-phosphate is converted into glucose-6-phosphate

• Enzyme used is phosphoglucomutase

Describe galactosemia.

• Increasing blood galactose conc. due to inability to metabolize galactose

• Inborn error of metabolism

• 1 in 35,000 births

• Caused by inherited defects in uridyl transferase (most common) or 4-epimerase

• Accumulation of galactose-1-p in liver will inhibit galactose kinase and glycogen phosphorylase resulting in hypoglycemia

What are the effects of galactosemia?

• Galactose reduced in eye by aldose reductase to form dulcitol which accumulates and causes cataracts (characteristic feature of galactosemia)

• Enlargement of liver, jaundice, severe mental retardation

Describe galactosuria.

• Excretion of galactose in urine

• Treatment: lactose-free diet

• Won’t improve mental retardation so early detection is important