HMP shunt

1. HEXOSE
MONOPHOSPHATE
PATHWAY
(PENTOSE PHOSPHATE PATHWAY)
This is an alternate pathway to glycolysis and TCA cycle
for the oxidation of glucose.

2. SITE : It is located in a cytosol . The tissues such as liver,
adipose tissue , adrenal gland ,erythrocytes , testes and
lactating mammary gland are highly active in HMP Shunt.

3. REACTIONS OF THE PATHWAY
1)OXIDATIVE PHASE: G6PD Is an NADP dependent enzyme
that converts glucose 6 phosphate to 6 phosphogluconolactone. The
latter is then hydrolysed by the gluconolactone hydrolase to 6
phosphogluconate. Next reaction involving the synthesis of NADPH is
catalysed by 6 phosphogluconate dehydrogenase to produce 3 keto 6
phosphogluconate which undergoes decarboxylation to give ribulose 5
phosphate.

4. 2) NON OXIDATIVE PHASE: It is concerned with
interconversion of three,four ,five and seven carbon monosacchrides.
Ribulose 5 phosphate is acted upon by epimerase to produce Xylulose 5
phosphate while ribose 5 phosphate ketoisomerase converts ribulose 5
phosphate to ribose 5 phosphate. The enzyme transketolase catalyse
the transfer of two carbon moiety from xylulose 5 phosphate to ribose 5
phosphate to form GA3P and sedoheptulose 7 phosphate.Transketolase
is dependent on TPP and Mg ions. Transaldolase brings about transfer of
3 carbon from S7P to GA3P to form fructose 6 phosphate and erythrose
4 phosphate.

6. REGULATION OF HMP SHUNT
# The entry of G6P into HMP pathway is controlled by
concentration of NADPH.
#NADPH is inhibitor of G6P DH.
# The Synthesis of G6P DH is induced by increased
insulin/glucagon after a meal.
SIGNIFICANCE: HMP Pathway generates two important
products
1. Pentose
2. NADPH

7. IMPORTANCE OF NADPH
#It is required for reductive biosynthesis of fatty acids and steroids.
#It is used in synthesis of certain amino acids involving the enzyme
Glutamate dehydrogenase.
#Microsomal cytochrome P 450 brings about detoxification of drugs
involving NADPH.
#Phagocytosis by WBC requires supply of NADPH.
#NADPH produce in RBC preserve the integrity of RBC membrane.

8. #GLUTATHIONE:Lipids , proteins and DNA are protected
from H2O2 by an antioxidant reactions involving NADPH. Glutathione
(reduced, GSH) detoxifies H2O2, peroxidase catalyses this reaction.
NADPH is responsible for regeneration of reduced glutathione from
oxidised one.

10. G6P DH deficiency causes Hemolytic
Anemia: Mutations cause deficiency of G6P DH with consequent
impairment of NADPH. Detoxification of H2O2 is inhibited and cellular
damage results- Lipid peroxidation leads to RBC membrane breakdown
and hemolytic anemia.

11. GLUCONEOGENESIS
The synthesis of glucose from non carbohydrate compounds
(lactate , pyruvate , glucogenic amino acids, glycerol) is known
as GLUCONEOGENESIS.

12. IMPORTANCE OF GLUCONEOGENESIS:
Glucose plays a key role in metabolism and is a continuous
supply of energy for our body.
For example: 1) Brain , RBC, Kidney are totally dependent on
glucouse for continous supply of energy.
2) Glucose is the only source of energy for skeletal muscles.
3) In fasting gluconeogenesis must occur to meet the basal
requirements of the body.
4) It effectively clears certain metabolities from blood
(lactate,glycerol).

13. LOCATION:
Gluconeogenesis occurs mainly in cytosol. Most common
sites are LIVER and KIDNEY.
REACTIONS :
Gluconeogenesis closely resembles glycolysis , but the 3
irreversible reactions of glycolysis are bypassed by alternate
enzymes. These three steps are:
1) Conversion of pyruvate to phosphoenol pyruvate .
2)Conversion of fructose1,6-bisphosphate to fructose 6
phosphate.
3)coversion of glucose 6 phosphate to glucose.

15. 1)CONVERSION OF PYRUVATE TO
PHOSPHOENOL PYRUVATE:
This takes place in two steps:
1. PYRUVATE CARBOXYLASE is biotin dependent
mitochondrial enzyme that coverts pyruvate to oxaloacetate
in presence of ATP and CO2.
2. Oxaloacetate has to be transported to cytosol to be used in
gluconeogenesis. In cytosol PHOSPHOENOL PYRUVATE
CARBOXYKINASE coverts oxaloacetate to PEP by using GTP as
a phosphorylating agent.
{As mitochondrial memb is impermeable to oxaloacetate , it is coverted
to malate and then transported to cytosol. In cytosol oxaloacetate is
regenerated from malate by an enzyme MDH.}

16. pyruvate oxaloacetate PEP
Pyruvate
carboxylase
PEP Carboxykinase
HCO3
+ ATP
ADP
+ Pi
GTP GDP +
CO2

17. 2) Conversion of fructose 1,6-
bisphosphate to fructose 6-phosphate:
The enzyme fructose 1,6- bisphosphatase coverts F16BP to
F6P. This enzyme requires Mg ions. It is absent in smooth
muscles and heart muscles.
Fructose 1,6 bisphosphate Fructose 6 phosphate
Fructose-1,6
bisphosphatase

18. 3)Conversion of Glucose 6 phosphate
to Glucose:
Glucose 6 phosphatase converts G6P to glucose. It is mostly
present in liver and kidney but absent in muscle,brain and
adipose tissue.
Glucose 6 phosphate Glucose
Glucose 6
phosphatase

19. REGULATION OF GLUCONEOGENESIS:
#Hormone glucagon stimulates gluconeogenesis by two
mechanisms:
1. Active form of Pyruvate Kinase is coverted to inactive form
through the mediation of cyclic AMP brought about by
glucagon. Therefore reduced conversion of PEP to pyruvate
occurs.
2. Glucagon reduces the concentration of F26BP. This
compound allosterically inhibits PFK and activates F16BPase.
# ACETYL CoA promotes gluconeogenesis: acetyl CoA
allosterically activates pyruvate carboxylase resulting in
enhanced glucose production.

20. ALCOHOL INHIBITS
GLUCONEOGENESIS
Ethanol oxidation in the liver to acetaldehyde by the enzyme
alcohol dehydrogenase utilizes NAD. The excess NADH
produced in liver interferes with gluconeogenesis.
Ethanol + NAD Acetaldehyde + NADH + H
Pyruvate + NADH + H Lactate + NAD

21. CORI CYCLE (GLUCONEOGENESIS
FROM LACTATE)
Lactate produced by skeletal muscles is a major precursor for
gluconeogenesis. Lactate or pyruvate produced in muscle
cannot be utilized for the production of glucose due to the
absence of certain enzymes(G6Pase and F16BPase).Therefore
lactate is carried from the muscle through blood to liver
where it is oxidized to pyruvate. Pyruvate so produced is
converted to glucose by gluconeogenesis.

23. Glycogen synthesis
(Glycogenesis)
• Glycogen is the storage form of carbohydrates
in the human body.
• The major sites of storage are liver and
muscle.
• Glycogenesis is the synthesis of glycogen from
blood glucose for storage in the body.

24. The various steps involved are:-
• ACTIVATION OF GLUCOSE
UDP glucose is formed from glucose-1-
phosphate and UTP by the enzyme UDP-
glucose pyrophosphorylase.
glucose-1-phosphate + UTP UDP-glucose + Ppi
UDP glucose
phosphorylase

25. Glycogen Synthase
• Glucose moiety from UDP glucose is
transferred to glycogen primer(glycogenin).
• Primer is essential to accept glycosyl unit. It is
made up of protein-carbohydrate complex.
Glycogen primer(n) Glycogen(n+1) +UDP
+ UDP glucose
• In next step, activated glucose units are added
by the enzyme glycogen synthase. The glucose
unit is added to the non reducing(outer) end
Glycogen Synthase

26. of the primer to form an alpha-1,4 glycosidic
linkage and UDP is liberated.
BRANCHING ENZYME
• This enzyme creates alpha-1,6 linkage.
• 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. This enzyme amylo-[1,4] [1,6]-
transglucosidase forms alpha-1,6 linkage.

27. • To this newly created branch, further glucose
units can be added in alpha-1,4 limkage by
glycogen synthase.
Important points
 The key enzyme for glycogenesis is glycogen
synthase, the activity of which is decreased by
glucagon and epinephrine but is enhanced by insuli,
under the stimulus of hyperglycemia.
 Glycogen synthase enzyme becomes inactive on
phosphorylation.
 The covalent modification of this enzyme is by a
cyclic AMP mediated cascade.

29. Regulation of glycogenesis

30. GLYCOGEN STORAGE DISEASES
The metabolic defects concerned with the glycogen synthesis
and degradation are collectively reffered to as glycogen
storage diseases. These disorders are characterised by
deposition of normal or abnormal type of glycogen in one or
more tissues.

31. VON GIERKE’S DISEASE(TYPE1)
This disorder results invarious boochemical manifestations
1.fasting hypoglycemia:due to the defect in the
enzyme glucose 6 phosphate enough glucose is not
released from the liver
2.lactic acidemia:glucose is not synthesised from the
lactate produced in the muscle and liver. Therefore
lactate level in the blood increases.
3.hyperlipidemia:there is the blockade in a
gluconeogenesis hence more fat is mobilised to meet
energy requiremenats of the body.
4.hyperuricemia:elevated plsma levels of uric acid are
often seen.

32. POMPE’S DISEASE(TYPE2):
1.It is due to the defect of enzyme lysosomal a-1,6
glucosidase.
2.All the organs are involved.
3.glucogen accumlates in lysosome in almost all the
tissues,heart is mostly involved,enlarged liver nd heart,death
occurs at an early age due to heart failure,nervous system is
also affected.

33. CORI’S DISEASE(type3)
1.It is due to the defect of enzyme amylo a-1,6 glucosidase.
2.Liver, muscle and heart lucocytes are involved.
3.Branched chain glycogen accumaltes,liver is enlarged.

34. ANDERSON’S DISEASE(TYPE4)
1.It is due to the defct of enzyme glucosyl 4,6transferase.
2.Most of the tissues are involved.
3.Glyogen with only few branches accumlate,impairement in
a liver function.

35. McARDLE’S DISEASE(TYPE5)
1.It is due t defect of enzyme muscle glycogen phosphorylase.
2.Skeleton muscles are involved.
3. Muscle gylcogen store is very high,not available during
exercise, muscles may get damaged due to inadequate energy
supply.

36. HER’S DISEASE(TYPE6)
1. It is due to the defect of enzyme liver glyogen
phosphorylase.
2. Liver is involved.
3.Liver is enlarged,liver glycogen cannot form glucose,mild
hypoglycemia is seen.

37. TARUI’S DISEASE(TYPE7)
1. It is due to the defct of enzyme phosphofructokinase.
2. Skeleton and erythrocytes are involved.
3.Muscle cramps due to the exercise,blood lactate not
elevated,hemolysis occurs.

38. AMPHIBOLIC NATURE OF TCA CYCLE:
It is both catabolic and anabolic in nature hence regarded as
Amphibolic. TCA is involved in Gluconeogenesis , Transamination and
Deamination.
IMPORTANT ANABOLIC REACTIONS ARE:
1.Oxaloacetate and a- ketoglutarate respectively serve as precursors for
synthesis of Aspartate and Glutamate which inturn are required for
synthesis of non essential amino acid.
2.Succinyl CoA is used for synthesis of porphyrin and heme.
3.Mitochondrial citrate is transported to cytosol where it is cleaved to
provide acetyl CoA for biosynthesis of fatty acids.