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Isoenzymes 2020

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337 views13 pages

Isoenzymes 2020

Uploaded by

mobashsharulalam3
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Isoenzymes

Isoenzymes
• Isoenzymes (isozymes) are enzymes that catalyze identical
chemical reactions but are composed of different amino acid
sequences.
• Isozymes are isoforms (closely related variants) of enzymes.
• Isoenzymes are produced by different genes.
• Isozymes are usually the result of gene duplication, polyploidisation
(Polyploid cells and organisms are those containing more than two
paired sets of chromosomes) or nucleic acid hybridization.

• Example:
• Hexokinase is a regulatory enzyme.
• It catalyzes the entry of free glucose into the glycolytic pathway
• glucokinase is an isoenzyme of hexokinase.
Biological importance of isozymes
• Isoenzymes are useful biochemical markers and can be measured
in the bloodstream to diagnose medical conditions.
• Hexokinase is a regulatory enzyme. It catalyzes the entry of free
glucose into the glycolytic pathway,
• There are four isozymes (designated I to IV) of hexokinase.
• Properties of hexokinases I – III :
1. Located in muscle
2. High affinity for glucose (half-saturated at about 0.1 mM)
3. Very low Km value
4. Allosterically inhibited by their product, glucose 6-phosphate,
whenever the cellular concentration of glucose 6-phosphate rises
above its normal level.
• Properties of hexokinases IV (glucokinase):
• 1. Located in lever
• 2. Low affinity for glucose (half-saturated at about 10 mM)
• 3. High Km value of hexokinase IV allows its direct regulation by the
level of blood glucose (Fig. 15–16).
Characteristics of isozymes

• Isozymes are variants of the same enzyme


• Produced by different genes
• Composed of similar but not identical, amino acid sequences
• Binds to same substrate and catalyse same reactions
• Differ in enzyme kinetics (differ in Km and Vmax values).
• Differ in regulatory properties ( glucokinase, a variant
of hexokinase which is not inhibited by glucose 6-phosphate.)
• Differ in the cofactor use (NADH or NADPH for dehydrogenase
isozymes)
• Differ in subcellular distribution (soluble or membrane-bound)
• Permit the fine-tuning of metabolism to meet the particular
needs of a given tissue or developmental stage
• In many cases they share a common evolutionary origin.
Biological importance of isozymes
4.Reversibly inhibited by a regulatory enzyme specific to liver.
The inhibition is much tighter in the presence of the allosteric
effector fructose 6-phosphate.
5. Hexokinase IV is not inhibited by glucose 6- phosphate and is not
saturated at 10 mM glucose, therefore, its activity continues to
increase as the glucose concentration rises to 10 mM or more.
Immediately after a carbohydrate-rich meal, high amount of glucose
enters in the hepatocyte and competes with fructose 6-phosphate
for binding and causes dissociation of inhibitory enzyme from
hexokinase IV, relieving the inhibition.
• During a fast, when blood glucose drops below 5 mM, fructose 6-
phosphate triggers the inhibition of hexokinase IV, so the liver does
not compete with other organs for the scarce glucose.
• Thus different hexokinase isozymes of liver and muscle reflect the
different roles of these organs in carbohydrate metabolism. Muscle
consumes glucose for energy production, whereas liver maintains
blood glucose homeostasis (equilibrium).
Biological importance of isozymes
Biological importance of isozymes
• Lactate dehydrogenase is an enzyme found in nearly all living
cells. LDH catalyzes the conversion of lactate to pyruvate and
vice versa, as it converts NAD⁺ to NADH and vice versa.
• It exists as five different isozymes.
• All LDH isozymes contain four polypeptide chains, each type
contain a different ratio of two kinds of polypeptides (H-form and
M-Form).
• The M (for muscle) chain and the H (for heart) chain are encoded
by two different genes.
• In skeletal muscle the predominant isozyme contains four M
chains, and in heart the predominant isozyme contains four H
chains.
• Other tissues have some combination of the five possible types of
LDH isozymes:
Biological importance of isozymes
• These differences in the isozyme content can be used to
assess the timing and extent of heart damage due to
myocardial infarction (heart attack).
• Damage to heart tissue results in the release of heart LDH
into the blood.
• Shortly after a heart attack, the blood level of total LDH
increases, and there is more LDH2 than LDH1.
• After 12 hours the amounts of LDH1 and LDH2 are very
similar, and after 24 hours there is more LDH1 than LDH2.
• The different LDH isozymes have significantly different
values of Vmax and Km, particularly for pyruvate.
• The properties of LDH4 favor rapid reduction of very low
concentrations of pyruvate to lactate in skeletal muscle,
whereas isozyme LDH1 favor rapid oxidation of lactate to
pyruvate in the heart.
Clinical importance of isozymes
• Some clinically important isoenzymes are as follows-
• 1) Creatine Kinase (CK) is an enzyme found primarily in the
heart and skeletal muscles, and to a lesser extent in the brain
but not found at all in liver and kidney.
• Small amounts are also found in lungs, thyroid and adrenal
glands.
• Significant injury to any of these organs will lead to a
measurable increase in CK levels.
• Normal Value- serum activity varies from 10-50 IU/L at 30°C.
• Elevations are found during the following diseases:
• Myocardial infarction
• Crushing muscular trauma
• Brain injury
• Hypothyroidism
• Hypokalemia :Hypokalemia is a low level of potassium in the blood serum.
Symptoms may include feeling tired, leg cramps, weakness, and constipation.
•
Clinical importance of isozymes
After myocardial infarction- serum value is found to increase
within 3-6 hours, reaches a peak level in 24-30 hours and
returns to normal level in 2 - 4 days.
• CK is a sensitive indicator in the early stages of myocardial
ischemia.
• CK Isoenzymes
There are three Isoenzymes.
• Each iso enzyme is a dimer composed of two protomers
(protomer is the structural unit of an oligomeric protein) ‘M’ (for
muscles) and ‘B’( for Brain).
• The three possible iso enzymes are:
Isoenzyme Type Composition Location

CK 1 BB Brain
CK 2 MB Heart Muscle
CK 3 MM Skeletal muscle,
heart muscle
Clinical importance of isozymes
• 2) Hepatic isoenzyme- Various liver diseases such as primary
or secondary cancer, biliary obstruction lead to increase the liver
isoenzyme level.
• 3) Bone isoenzyme- Osteoblastic bone tumors and
hyperactivity of osteoblasts involved in bone remodeling (eg,
Paget’s disease) increase the bone isoenzyme.
• 4) Placental isoenzyme - increases during last six weeks of
pregnancy.
• 5) The intestinal isoenzyme- increased in patients with
cirrhosis
6) Oncogenic marker isoenzymes- some isoenzymes are
associated with tumors such as Regan and Nagao
isoenzymes.
Regan isoenzyme is elevated in various carcinoma such as
breast, lungs, colon, ovaries and uterus.
• Nagao isoenzyme is observed in metastatic carcinoma of
pleural surfaces and adenocarcinoma of pancreas and bile duct.
Pagets Disease

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