URONIC ACID PATHWAY

URONIC ACID PATHWAY

• Product of Uronic acid pathway in humans is

Glucuronic acid
• Glucuronic acid & glucose: similar in structure
 URONIC ACID PATHWAY
• Aldehyde group is protected and glucose is oxidised C6
becomes COOH & Product formed is Glucuronic acid
 URONIC ACID PATHWAY –
Biomedical importance

•Alternate pathway of metabolism of glucose

• Another Oxidative pathway: End Product is Glucuronic acid

• No production of ATP: 1 UTP utilised: No CO 2 liberated

• Organs: mainly liver

•Organelles: Cytosol & ER

 URONIC ACID PATHWAY –
Biomedical importance

•Lower animals (but not humans and other primates )

synthesise ascorbic acid by this pathway.

• Humans cannot synthesise vitamin C by this pathway: lack L-

gulonolactone oxidase.

•Hence Vitamin C has become a dietary essential in humans

 WHY GLUCURONIC ACID IS IMPORTANT ?
Active form of glucuronic acid: UDP- Glucuronate
• Essential for synthesis of GAGs /MPS
• Addition of CHO groups to proteins: Glycoproteins
• Excretion of drugs & hormone metabolites (by conjugation (2-
acetylaminofluorene (a carcinogen), aniline, benzoic acid,
meprobamate (a tranquilizer), phenol, and many steroids)
• Xenobiotics: Elimination of foreign substances
• Bilirubin: by conjugation with glucuronic acid
• Mainly in liver
• Glucuronidation: most frequent conjugation reaction.
 Synthesis of vitamin C from
Glucuronic acid

Absent in man, simians,

L- gulonolactone rodents, bats, guinea pigs
oxidase Present in birds, reptiles
 INBORN ERRORS OF URONIC ACID PATHWAY

Essential Pentosuria:
•Garrod’s tetrad(albinism, alkaptonuria, cystinuria, and
pentosuria).
•Rare : AR disorder.
•Deficiency of enzyme Xylitol Dehydrogenase.
•Excretion of L-Xylulose in urine.
•Positive benedict’s test.
•Positive Bial’s test (for pentoses).
•Lab D/D for diabetes Mellitus.
Essential Pentosuria
 POLYOL PATHWAY

•Another Minor Oxidative Pathway

•Under normal conditions responsible for formation
of fructose from glucose in seminal vesicles for
spermatozoa (in brain) inactive in liver
• But becomes Critical in Diabetes Mellitus &
Galactosemia
• Especially in non- insulin dependant tissues lens, Peripheral
nerves & renal papillae.
• Responsible for the development of long term.
complications in uncontrolled DM: Diabetic Cataract
• Formed by reduction of glucose by aldose reductase to sorbitol,
• Oxidized to fructose.
• Glucose when converted to sorbitol, cannot diffuse out of the cell easily and gets
trapped there.
• Sorbitol is normally present in lens of eyes.
• In diabetes mellitus, when glucose level is high, the sorbitol concentration also
increases in the lens.
• Leads to osmotic damage of the tissue and development of cataract.
• Galactitol also causes cataract.
• Fructose is present in semen in large quantities.
• Produced by the polyol pathway.
• Polyol pathway is active: brain and fructose is seen in CSF.
• Inactive: liver.
 POLYOL PATHWAY
Increase glucose concentration in non-insulin sensitive tissues

Increased activity of Aldose Reductase

Increased formation of Sorbitiol

Trapping of Sorbitiol in tissues

Draws water into tissues by Osmosis

Cataract formation & peripheral

neuropathy (fall in myo-inositol levels)
 POLYOL PATHWAY
Aldose Reductase inhibitors:
• Drugs that inhibit Aldose Reductase
• Delay the onset of or even prevent these
complications
• Sorbitol accumulation, myoinositol depletion,
and diabetic cataract, neuropathy, nephropathy & even

retinopathy
• Modest success in human clinical trials
Aldose Reductase inhibitors