URONIC ACID PATHWAY (Glucuronic pathway)

URONIC ACID PATHWAY

(Glucuronic pathway)

This is an alternative oxidative pathway for glucose and is also known as the glucuronic pathway.
Concerned with the synthesis of glucuronic acid, pentoses, and vitamin, ascorbic acid (except in primates and guinea pigs).
Dietary xylulose enters the uronic acid pathway through which it can participate in other metabolisms.
Glucuronate is a highly polar molecule which is incorporated into proteoglycans as well as combining with bilirubin and steroid hormones; it can also be combined with certain drugs to increase their solubility.

Steps in Uronic acid pathway:

(A) Formation of UDP glucronate

Glucose 6 phosphate is first converted to glucose 1 phosphate
UDP glucose is then synthesized by enzyme UDP glucose pyrophosphorylase
Till this step, it is same as glycogenesis
UDP glucose dehydrogenase oxidizes UDP glucose to UDP glucuronate
UDP glucuronate is a metabolically active form of glucuronate which is utilized from the conjugation of many substances like bilirubin, steroid hormones, and drugs
UDP glucuronate is also required for the synthesis of glycosaminoglycans and proteoglycans

(B) Conversion of UDP-glucuronate to L gulonate

UDP glucuronate loses its UDP moiety in a hydrolytic reaction and releases D-glucuronate which is reduced to L-gulonate by an NADPH reaction.

Fate of L-gulonic acid:

(a) Synthesis of ascorbic acid:

L-Gulonic acid is the direct precursor of Ascorbic acid, in those animals which are capable of synthesizing this vitamin.
In those animals, synthesis of vitamin C (Ascorbic acid) takes place.

(b) Fate of L-Gulonic Acid in Humans:

In man and other primates as well as guinea pigs ascorbic acid cannot be synthesized.
The enzyme L-gulonolactone oxidase which converts gulonate to ascorbic acid is absent in them.
Therefore, vitamin C has to be supplemented in the diet for these animals.
L-Gulonic acid is oxidized to 3-ketoglulonate, which is then decarboxylated to the pentose L-Xylulose.
L-xylulose is converted to a D-xylulose via xylitol by a reduction followed by oxidation.
The D-xylulose can enter hexose monophosphate shunt.

Importance of uronic acid pathway:

It provides UDP-glucuronic acid, which is the active form of glucuronic acid
Conjugation of bilirubin
Conjugation of steroids
Conjugation of various drugs which will make them more water soluble and more easily excreatable.
Synthesis of glycosamino glycans (GAG).

Effect of drugs on uronic acid pathway:

Administration of barbital, aminopyrine, antipyrine, chlorobutanol significantly increases the uronic acid pathway to achieve more synthesis of glucuronate from glucose, leading to the availability of more glucuronate for conjugation purpose.
Certain drugs were found to enhance the synthesis of ascorbic acid in rats.

Essential pentosuria:

Rare genetic disorder related to the deficiency of NADP dependent. enzyme xylitol dehydrogenase and xylulose reductase. The incidence is 1 in 2,500 births.
Due to any of these enzyme defect xylulose cannot be converted to xylitol.
The affected secrete large amounts of L-xylulose in urine and gives a
positive Benedict’s test.
Essential pentosuria is asymptomatic and the individuals suffer from no ill-effects, but it should be differentiated from diabetes mellitus.
lt has been reported that the administration of drugs aminopyrine and
antipyrine increases the excretion of L-xylulose in pentosuric patients.

Summary:

The uronic acid pathway is an alternative pathway for the oxidation of glucose that does not provide a means of producing ATP, but is utilized for the generation of the activated form of glucuronate, UDP-glucuronate.
The uronic acid pathway of glucose conversion to glucuronate begins by conversion of glucose-6-phosphate is to glucose-1-phosphate by phosphoglucomutase, and then activated to UDP-glucose by UDP-glucose pyrophosphorylase.
UDP-glucose is oxidized to UDP-glucuronate by the NAD⁺-requiring enzyme, UDP-glucose dehydrogenase.
UDP-glucuronate then serves as a precursor for the synthesis of iduronic acid and UDP-xylose and is incorporated into proteoglycans and glycoproteins or forms conjugates with bilirubin, steroids, xenobiotics, drugs and many compounds containing hydroxyl (–OH) groups.

References:

Textbook of Biochemistry-U Satyanarayana
Textbook of Biochemistry-DM Vasudevan
https://www.scribd.com/document/328465491/2-4-Biochemistry-Tca-Hmp-and-Uronic-Acid-Pathway
https://microbenotes.com/uronic-acid-pathway/
https://www.slideshare.net/YESANNA/uronic-acid-pathway

Online Biochemistry Notes