2. Other Metabolic Pathways Of Glucose Flashcards
Branching enzymes
During glycogen synthesis,
i. The glycogen synthase can add glucose units only in alpha-1,4 linkage. A branching enzyme is needed to create the alpha-1,6 linkages.
ii. When the chain is lengthened to 11 - 12 glucose residues, the branching enzyme will transfer a block of 6 to 8 glucose residues from this chain to another site on the growing molecule. The enzyme amylo-[1,4]→[1,6]- transglucosidase (branching enzyme) forms this alpha-1,6 linkage (Fig. 9.37).
iii. To this newly created branch, further glucose units can be added in alpha-1,4 linkage by glycogen synthase.
Explain polyol pathway
The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.
Cells use glucose for energy. This normally occurs by phosphorylation from the enzyme hexokinase. However, if large amounts of glucose are present (as in diabetes mellitus), hexokinase becomes saturated and the excess glucose enters the polyol pathway when aldose reductase reduces it to sorbitol. This reaction oxidizes NADPH to NADP+. Sorbitol dehydrogenase can then oxidize sorbitol to fructose, which produces NADH from NAD+. Hexokinase can return the molecule to the glycolysis pathway by phosphorylating fructose to form fructose-6-phosphate. However, in uncontrolled diabetics that have high blood glucose - more than the glycolysis pathway can handle - the reactions mass balance ultimately favors the production of sorbitol.
Glucose when converted to sorbitol, cannot diffuse out of the cell easily and gets trapped there. Sorbitol is normally present in lens of eyes. But in diabetes mellitus, when glucose level is high, the sorbitol concentration also increases in the lens. This leads to osmotic damage of the tissue and development of cataract. Galactitol also causes cataract (see under galactose metabolism).
Fructose is present in semen in large quantities. It is produced by the polyol pathway. The polyol pathway is active in brain and fructose is seen in CSF. This pathway is inactive in liver.
Essential pentosuria
It is an inborn error of metabolism.
In the pathway, L-xylulose is converted to D-xylulose by two enzymes, xylitol dehydrogenase and xylulose reductase.
Absence of any of these enzymes leads to the pentosuria.
L-xylulose is excreted in urine and gives a positive Benedict’s test.
This condition does not produce any harm;but it should be differentiated from diabetes mellitus.
Describe von Gierke’s disease.
It is also known as Glycogen Storage Disease type I.
In this disease glucose six phosphatase is is deficient. The symptom is fasting hypoglycaemia that does not respond to stimulation even my adrenaline adrenaline because the liver is not able to utilise glucose.
Hyperlipidaemia due to excessive use of fatty acid lactic acidosis and ketosis are the symptoms.
Due to excess glucose six phosphate it is channelled to the HMP pathway and an excess of ribose and other nucleotides are formed which leads to excess of uric acid in the urine formed from the excess nucleotides. This leads to hyperuricemia.
Due to accumulation of unused glycogen in liver it leads to hepatomegaly and liver cirrhosis.
Treatment is to give small quantity of food at frequent intervals.
G6PD deficiency?
In cells oxidants are formed as a result of metabolic processes. These oxidants can damage and cause lysis of the cells. These oxidants are reduced and made harmless by glutathione, with the help of glutathione reductase enzyme. For glutathione reductase to function it requires NADPH. This is where G6PD is required as it is needed to convert NADP+ into NADPH. Due to deficiency of G6PD, NADPH won’t be produced and lack of glutathione leads to cell lysis by oxidants.
It is the most common enzyme deficiency seen in clinical practice. The defect is transmitted as an X-linked recessive trait.
ii. It will lead to drug-induced hemolytic anemia. The deficiency is manifested only when exposed to certain drugs or toxins, e.g. intake of antimalarial drugs like primaquine. Primaquin stimulates peroxide formation inside RBC. In GPD deficient cells, the level of NADPH is low; hence further production of peroxides will lead to cell lysis.
Similarly, ingestion of toxic glycosides present in fava beans may have similar effect (Favism). iv. Sulpha drugs and furadantin may also precipitate the hemolysis. This will lead to
jaundice and severe anemia.
v. The geographical distribution of GPD deficiency correlates well with the malarial endemicity. The enzyme deficiency offers resistance to plasmodium infection (See Chapter 22). The parasite requires reduced glutathione for its survival, which will not be available in adequate amounts in deficiency of GPD. GPD deficiency is reported from almost all States of India.
