DEPARTMENT OF BIOCHEMISTRY

LEARNING OBJECTIVES

 DISCUSS the Pentose Phosphate Pathway as to:

1.1 biomedical importance
1.2 sites of occurence and pathway
1.3 enzymes and factors involved
1.4 differentiate from Glycolysis
1.5 relationship with erythrocyte integrity
1.6 disorders associated with this pathway
 DISCUSS the Uronic pathway as to:
2.1 biomedical importance and products
2.2 production of ascorbic acid in lower animals
 DESCRIBE the importance and metabolic
pathway of amino sugar (hexosamine)
synthesis
 DISCUSS the Polyol pathway and its products
and its biomedical importance
 DISCUSS fructose metabolism
 DISCUSS the events that happen in the unfed
or fasting state
 DISCUSS Gluconeogenesis as to:
7.1 biomedical importance
7.2 site, process, substrates, enzymes
involved
7.3 production of PEP from pyruvate
7.4 enzyme and regulation of anapleurotic
step
 DISCUSS the regulation of key enzymes
 DISCUSS the Cori cycle and its importance
 DISCUSS glucose-alanine (Cahill) cycle during
the starvation state
 ENUMERATE hormones that affect CHO
metabolism
 ENUMERATE conditions that can give
hypoglycemia and hyperglycemia
 DESCRIBE the different types of Diabetes
Mellitus
 DISCUSS the relationship of high glucose levels
with cataract formation
THE PENTOSE PHOSPHATE
PATHWAY
 Also known as the PHOSPHOGLUCONATE
PATHWAY, HEXOSE MONOPHOSPHATE
SHUNT and WARBURG DICKENS pathway
 Can occur anaerobically
 Alternate route for glucose oxidation in the
fed state
 Occurs in the CYTOSOL in the organs active
in reductive synthesis
 DOES NOT GENERATE ATP
2 MAJOR FUNCTIONS OF PPP

 NADPH production ( generated at the

Oxidative/Irreversible phase )

 Production of RIBOSE (generated at the

Nonoxidative/ Reversible Phase)
PPP vs GLYCOLYSIS
PPP
 Occurs in the cytosol
 Occurs in cells concerned
with reductive synthesis
 Coenzyme is NADP+
 Occurs aerobically or
anaerobically
 Does not require input of ATP
 Does not produce ATP
 Ribose production
 NADPH and CO2 production
GLYCOLYSIS
 Occurs in the cytosol
 Occurs in virtually all cells
 Coenzyme is NAD+
 Occurs aerobically and
anaerobically
 Requires input of ATP
 Produces ATP
 Does not produce ribose
 NADH+H production no CO2
The Oxidative Irreversible
Phase
The Nonoxidative
Reversible Phase
PPP AND ITS IMPORTANCE IN
ERYTHROCYTES

 NADPH produced provides for the reducing

equivalents of Methemoglobin Reductase

 NADPH keeps Glutathione in the reduced

state preventing accumulation of H202 that
can possibly cause RBC lysis
NADPH AND ITS ROLE IN RBCs

 Keeps Glutathione in the reduced state

DISORDER ASSOCIATED WITH
PPP
 GLUCOSE-6-PHOSPHATE
DEHYDROGENASE (G6PD ) DEFICIENCY
 Most common enzymopathy worldwide

the missing product of this enzyme is?

what tissue will be most affected by the
absence of this product and why?
what will be the clinical manifestation?
THE URONIC ACID PATHWAY

 Another alternative oxidative pathway for

glucose metabolism in the liver
 Has 3 important products:
1. GLUCORONATE - important for
conujugation reactions
2. ASCORBIC ACID - not produced in
humans due to absent GULONOLACTONE
OXIDASE enzyme
3. PENTOSES - D-xylulose which, as
glucose, may enter Glycolysis
Production of UDP
Glucoronate
The production
Of Ascorbate
And D-Xylulose
ABNORMALITIES IN THE URONIC
ACID PATHWAY

 ESSENTIAL PENTOSURIA - absence of

enzyme that reduces L- xylulose to xylitol
- no known serious physiologic effects
 DRUGS LIKE BARBITURATES AND
CHLOROBUTANOL - increase the rate at
which glucose enters the uronate pathway 
increased glucoronate and L-gulonic acid
THE POLYOL PATHWAY

 Responsible for fructose formation from glucose

 May be the source of fructose in the CSF and
seminal fluid
 Does not occur in the liver
 ALDOSE REDUCTASE reduces glucose or
galactose to sorbitol or galactitol respectively
 This pathway is active in tissues that are not
insulin-sensitive : lens, renal glomeruli and
peripheral nerves
 Sorbitol (or D-glucitol) causes osmotic damage
and depletion of myoinositol
POLYOL PATHWAY
HEXOSAMINE PATHWAY

 Important components of : glycoproteins,

glycosaminoglycans and gangliosides

 The major amino sugars are : glucosamine,

galactosamine, mannosamine and sialic acid
METABOLISM IN THE FASTING
STATE
GLYCOGENOLYSIS
GLUCONEOGENESIS
THE FASTING STATE
EVENTS IN THE FASTING STATE

 Blood sugar begins to decline

 Insulin decreases and Glucagon ( or
Epinephrine) increases
 Initially blood sugar is maintained by
GLYCOGENOLYSIS ( activation of Glycogen
Phosphorylase )
 When glycogen stores have been depleted,
the body turns to other sources of glucose 
GLUCONEOGENESIS
GLUCONEOGENESIS

 Synthesis of Carbohydrates from non-

carbohydrate sources

 SUBSTRATES FOR GLUCONEOGENESIS:

1. Lactate
2. Glycerol
3. glucogenic amino acids
4. Propionate - odd-numbered fatty acid
BIOMEDICAL IMPORTANCE
1. To SUPPLY GLUCOSE to the following when
glycogen supplies have been depleted:
- Brain and erythrocytes
- Contracting skeletal muscle
- Fetus in pregnancy
- Lactating mammary gland
- Retina, lens, renal medulla etc

2. To clear products of metabolism : lactate and

glycerol
ORGANS CAPABLE OF
GLUCONEOGENESIS

 LIVER

 KIDNEYS
FOUR UNIQUE ENZYMES OF
GLUCONEOGENESIS

 PYRUVATE CARBOXYLASE
- catalyzes the conversion of pyruvate to
oxaloacetate
- catalyzes the ANAPLEUROTIC STEP
- occurs in the mitochondria
 PHOSPHOENOLPYRUVATE CARBOXYKINASE
- decarboxylation of oxaloacetate to PEP
- occurs in the cytoplasm
 FRUCTOSE-1,6-BIPHOSPHATASE
- converts fructose-1,6-biphosphate to
fructose-6-phosphate

 GLUCOSE-6-PHOSPHATASE
- mobilizes glucose-6-phosphate to free
glucose
Reversal of Pyruvate to PEP
PEP to Glucose
Entry points of substrates
CORI CYCLE

 Also known as LACTIC ACID CYCLE

 Recycles lactic acid from skeletal muscle and

erythrocytes back to glucose in the liver via
gluconeogenesis
GLUCOSE ALANINE CYCLE

 Also known as CAHILL CYCLE

 Occurs during the fasting state
 Pyruvate is transaminated to Alanine in the
skeletal muscle  taken into the liver 
pyruvate carbon skeleton is recycled back to
glucose via gluconeogenesis
 Thus, indirectly, the muscle is able to donate
some of its glycogen to the systemic
circulation via pyruvate
Cori Cycle and Cahill Cycle
RECIPROCAL CONTROL OF
GLYCOLYSIS AND
GLUCONEOGENESIS
1. COMPARTMENTALIZATION of enzymes
( Pyruvate Kinase vs Pyruvate Carboxykinase)
2. INDUCTION AND REPRESSION OF KEY ENZYMES
Glucagon - stimulate activity of PEP Carboxykinase
Cortisol - synthesis of 4 key enzymes of
Gluconeogenesis
Insulin - represses synthesis of all 4 key enzymes of
Gluconeogenesis and stimulate the 3 Glycolytic key
enzymes
3. ALLOSTERIC (SUBSTRATE ) MODIFICATION
Pyruvate Carboxylase - Acetyl CoA is positive
effector
Pyruvate Dehydrogenase - Acetyl CoA is a
negative effector
ALLOSTERIC MODIFICATION CONTINUATION
Fructose-2,6-biphosphate - stimulate
Phosphofructokinase-1 and inhibit
fructose-1,6-biphosphatase = GO
GLYCOLYSIS
STOP GLUCONEOGENESIS
Glucose-6-phosphatase - inhibited by Pi and
glucose
4. COVALENT (HORMONAL) MODIFICATION OF
KEY ENZYMES
Glucagon + Epinephrine - stimulate the
formation of cAMP  activates cAMP-
dependent protein kinase:
EX:
Phosphorylation of PDH = inactive enzymes
Phosphorylation of Pyruvate Carboxylase =
active enzyme
Also Glycogen Phosphorylase vs Glycogen
Synthase
5. AVAILABILITY OF SUBSTRATES
• - presence/absence of glucose
SOURCES OF BLOOD GLUCOSE

 Dietary carbohydrates
 Glycogen
 Glucogenic amino acids
 Lactate
 Glycerol
4 CATEGORIES OF GENETIC
DEFICIENCIES IN CHO
METABOLISM
• Those involving hexoses
Ex: G6PD deficiency
• Those involving pentoses
Ex: pentosuria
• Those affecting glycogen metabolism
• Those related to abnormal glycolysis in RBCs
ex: pyruvate kinase deficiency
HORMONES THAT REGULATE
BLOOD GLUCOSE
 HYPOGLYCEMIC
Insulin - stimulus for release : hyperglycemia,
increased amino acids, FFA, sulfonylureas
 HYPERGLYCEMIC*
Glucagon - it opposes the action of Insulin
- stimulates hepatic glycogeno-
lysis and gluconeogenesis
Epinephrine and Norepinephrine - block
Insulin release
- increases muscle and hepatic
glycogenolysis
 Growth Hormone - stimulated by hypo-
glycemia, it decreases glucose up-
take in muscle and stimulates fat
mobilization
ACTH /Glucocorticoids - stimulate key enzymes
of gluconeogenesis and increases
protein mobilization
- it inhibits glucose utilization by
extrahepatic tissues

*These hormones are potentially DIABETOGENIC

CONDITIONS THAT CAN GIVE
HYPOGLYCEMIA

 Impaired fatty acid oxidation

 Glycogen storage disease - group of
hereditary diseases characterized by either
deposition of abnormal type of glycogen or
failure to mobilize glycogen due to defective
enzymes
- death is due to hypoglycemia or hepatic
failure
 Fructose-1,6-biphosphatase deficiency

 Pancreatic tumors : Insulinomas ( causes

oversecretion of Insulin)

 Insulin overdose

 Pregnancy

 Prematurity and low birth weight infants

CONDITIONS THAT CAN GIVE
HYPERGLYCEMIA

 Stress

 Overproduction of diabetogenic hormones

 Insulin : undersecretion, resistance to

effects, abnormal / defective insulin
DISEASES ASSOCIATED WITH
CARBOHYDRATE METABOLISM
 Lactic acidosis
 Glycogen storage diseases
 Glucose-6-phosphate dehydrogenase
deficiency
 Galactosemia
 Essential fructosuria and hereditary fructose
intolerance
 Diabetes Mellitus
TYPES OF DIABETES MELLITUS

 TYPE I / INSULIN DEPENDENT ( IDDM)

- insulinopenia
- dependent on exogenous insulin to sustain
life
- classically occurs in children and adolescents but
may occur at any age
- abrupt, acute and rapid onset of symptoms
- patients are usually thin in habitus
- ketosis prone
- normal Insulin sensitivity
- antibodies causing beta cell destruction identified
 TYPE II / NON INSULIN DEPENDENT ( NIDDM )
- usually occurs at age 40 and above but may
occur at any age
- usually onset is mild, insidious and gradual
- insulin secretion is variable
- insulin sensitivity is decreased
- not dependent on insulin but it may be required if non
responsive to drugs
- patients are usually overweight to obese
- stronger genetic / hereditary basis
- non-ketosis prone but prone to hyperosmolar coma
CRITERIA FOR THE DIAGNOSIS
OF DIABETES MELLITUS

1. SIGNS AND SYMPTOMS - presence of

Polyphagia, Polydipsia and Polyuria plus
weight loss and ketosis in IDDM
 ELEVATED FASTING BLOOD SUGAR
> 140 mg% on at least 2 separate occasions
 ORAL GLUCOSE TOLERANCE TEST ( OGTT)
CRITERIA:
Following ingestion of 1 gm/kg bw glucose:
Venous plasma glucose >200 mg% at 2 hours
and at least one other occasion during the 2
hour test ( two values >200 mg% must be
obtained )
 INCREASED HbA1c OR GLYCOSYLATED
HEMOGLOBIN - reflects glucose control for
the past 3 months
AT THE START OF THIS UNIT,
THIS WAS HOW YOU LOOKED OR
FELT….
NOW THAT YOU KNOW HOW THE
NORMAL BODY HANDLES CHO,
THIS IS YOU NOW
REMEMBER :
END OF LECTURE