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Q.1 -Discuss the steps of Uronic acid pathway, what is the biological significance of this pathway?

 Answer- 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 which is mainly used for detoxification of foreign chemicals and for the synthesis of Mucopolysaccharides. This pathway also produces Ascorbic acid in certain animals.

 The unutilized Glucuronate produced in this pathway is converted to Xylulose-5 P which is further metabolized through HMP pathway

Steps of Uronic acid pathway

 

 

 

 

 

 

 

 

 

 

 

 

Figure-1- showing the reactions of Uronic acid pathway

 1) Formation of UDP glucose

Glucose 6-phosphate is isomerized to glucose 1-phosphate in a reaction catalyzed by Phosphoglucomutase, which then reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyro phosphorylase, as occurs in glycogen synthesis. (Figure-1)

2) Formation of D- Glucuronic acid

UDPGlc is oxidized at carbon 6 by NAD-dependent UDPGlc dehydrogenase in a two-step reaction to yield UDP-glucuronate. (Figure 1)

UDP-glucuronate is the source of glucuronate for reactions involving its incorporation into Proteoglycans or for reactions of substrates such as steroid hormones, bilirubin, and a number of drugs that are excreted in urine or bile as glucuronide conjugates. UDP- G is hydrolyzed to form D- Glucuronic acid.

3) Formation of L- Gulonic acid

Glucuronate is first reduced by the NADPH dependent enzyme, Glucuronate reductase to form L- gulonate which is dehydrated in the presence of enzyme, Aldonolactonase to form L-gulono-δ-lactone, the direct precursor of ascorbate in those animals capable of synthesizing this vitamin, in an NADPH-dependent reaction. Removal of a pair of hydrogen atoms from L-gulono-δ-lactone, under the effect of enzyme L-gluconolactone oxidase leads to the formation of 2-keto gulono lactone which is finally converted to L ascorbic acid. (Figure-2)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2- showing the synthesis of ascorbic acid from D- glucuronic acid. The enzyme L- gluconolactone oxidase is absent in human beings and in certain animals as shown by the block at the step. D- Glucuronic acid in such species is converted to Xylulose-5-p through a number of steps, which enters Pentose phosphate pathway for further metabolism.

This pathway is used by plants and some animals for the synthesis of Ascorbic acid. In humans and other primates, as well as in guinea pigs, bats, and some birds and fishes, ascorbic acid cannot be synthesized because of the absence of L-gluconolactone oxidase. It is due to genetic deficiency of this enzyme. It appears that the capacity to synthesize ascorbic acid was lost in these species due to a mutation which was not lethal. These species require vitamin C in the diet. Thus a single enzyme defect in the Uronic acid pathway is responsible for inefficiency to synthesize ascorbic acid in primates.

4) Fate of L- Gulonate

Uronic acid pathway is connected to Pentose phosphate pathway through L-gulonate, since the latter can be converted to an intermediate of the Pentose phosphate pathway as follows-

 

 

 

 

 

L-Gulonate is oxidized to 3-keto-L-gulonate, which is then decarboxylated to L-Xylulose. L-Xylulose is converted to the D isomer by an NADPH-dependent reduction to xylitol, followed by oxidation in an NAD-dependent reaction to D-Xylulose. D- Xylulose is converted to converted to D-Xylulose 5-phosphate at the expense of ATP which is metabolized via the pentose phosphate pathway.(Figure-3)

 

 

 

 

 

 

 

 

 

 

 

Figure- 3- showing the fate of L- Xylulose

Biological significance of Uronic acid pathway- UDP glucuronate the active form of glucuronic acid, can readily donate the glucuronic acid component for the following functions-

1) Detoxification of foreign compounds and drugs- During detoxification, the glucuronate residues are covalently attached to these substances. Since glucuronate residues are strongly polar, their attachment imparts polar character to these substances, making them water-soluble and readily excretable. Bilirubin, certain hormones and drugs are made more polar for renal excretion in this manner.

2) Synthesis of Mucopolysaccharides-such as hyaluronic acid and heparin, which contain glucuronic acid as essential component.

 Q.2- What is the defect in essential Pentosuria? How can this be diagnosed? What are the clinical manifestations and how is this defect treated?

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A 35-year-old Lebanese Christian male was referred to the biochemical laboratory for the study of his mellituria. The urinary sugar had been discovered during a hospitalization for the repair of an inguinal hernia when the patient was 20 years of age, and he was then refused operation because of “diabetes.” Numerous blood sugar analyses were reported normal. The patient was in excellent health and had no symptoms of diabetes, but was concerned about his condition. L- xylulose was present excessively in urine. What is the probable diagnosis?

Answer- Pentosuria is the condition in which an unusual reducing substance, one of the pentose sugars, is constantly excreted in the urine and gives a positive reaction on testing with Benedict’s solution. It is a rare hereditary disease which has been included by Garrod (1923) among the inborn errors of metabolism. Its occurrence was first described in 1892, but since then only about 200 cases have been recorded in the literature, the disorder occurred almost entirely in the Jewish race.

Biochemical defect- The enzyme that causes conversion of L-Xylulose to Xylitol is deficient. As a result the excess of L-Xylulose is excreted in urine.

Clinical Manifestations- It may go unnoticed or it may be a chance finding on routine examination of urine. There are no signs and symptoms associated with it. Various drugs increase the rate at which glucose enters the uronic acid pathway. For example, administration of barbital or chlorobutanol to rats results in a significant increase in the conversion of glucose to glucuronate, L-gulonate, and ascorbate. Aminopyrine and antipyrine increase the excretion of L-xylulose in pentosuric subjects.

Diagnosis-It can be misdiagnosed with renal glycosuria or mild diabetes mellitus. The Qualitative Benedict’s test for reducing substances is given positive in this condition. Bial’s test and fasting blood glucose estimation can rule out renal glycosuria and diabetes mellitus.

The identification of urinary xylulose has been greatly facilitated by the introduction of paper chromatography.

Treatment- No treatment is required for this defect.

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