dr vivek joshi, md. introduction biomedical importance glycogenesis (glycogen synthesis) ...
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Dr Vivek Joshi, MD
Introduction
Biomedical importance
Glycogenesis (Glycogen Synthesis)
Glycogenolysis (Glycogen Breakdown)
Regulation of Glycogen Metabolism
Glycogen Storage Disease (GSD)
Branch
Glucose residues in a linear sequence are linked to each other by a
1→4 glycosidic linkage
Branched hompolysaccharide of D-glucose
Branches every 8-12 residues along the chain, linked as
1→6 linkages
Glycogen-Ideal storage form
NO OSMOTIC PRESSURE HIGHLY BRANCHED-READILY BROKEN DOWN-HORMONES
&ENZYMES WATER SOLUBLE MORE FREE GLUCOSE RESIDUES-NON REDUCING END
Gn
Nonreducing ends
Single reducing end bound to Glycogenin
Single reducing end bound to Glycogenin
Glycogen –Storage Form
Glycogen breakdown yields Glucose
Stores about 50-100gms of glycogen. Amounts to 200-300gms with water of hydration
Glycogen used for maintenance of blood glucose levels
Lasts about 12-14 hrs
MUSCLE Glycogen as a body energy store
Stores about 400-500gm in an average adult Not available for blood glucose maintenance due to
absent Glucose 6-phosphatase Provides energy during bursts of muscle activity
Carbohydrates in dietSporadicFrequency unreliable
GlycogenSignificant storageRapidly mobilized - fast responseTotal hepatic storage-enough to maintain blood glucose levels during a 12-14 hr fast
GluconeogenesisSlow in reacting to a fall in blood glucose levels
Source of Glucose in the body
Sites of Synthesis: Most cells of the body significantly in the liver
and the muscle Sub cellular site: Cytosol Steps:
Glucose uptake -GLUT2 and GLUT4 Conversion of Glucose to Glucose -6-P Conversion of Glucose-6-P to UDP-Glucose Elongation of chain: Glycogen Synthase
(Glycogen Fragment/Glycogenin to Initiate Glycogen synthesis)
Introduction of branches: Branching enzyme
Name Tissues Km,Glucose
Functions
GLUT I Most tissues (Brain, Red cells)
~1 mM Basal uptake of glucose
GLUT 2 Liver Pancreatic beta cells
~15 mM Uptake and release of glucose by the liver Beta –cell Glucose sensor
GLUT 3 Most tissues ~1 mM Basal uptake
GLUT 4 Skeletal muscle Adipose tissue
~5mM Insulin-stimulated glucose uptake ; Stimulated by exercise in skeletal muscleNormal Blood Glucose Level : 70-100 mg/dl
4-5.5 mmol/L
GLUCOSE TRANSPORTERS (GLUT)GLUCOSE TRANSPORTERS (GLUT)
Branching enzyme [ Amylo -(1 4) (1 6) transglucosidase] transfers 6-8 residues to the neighbouring branch to create a branch point[ α (1 6) linkage]
The above processes continues till a highly branched Glycogen is formed.
Rate limiting enzyme for synthesis of Glycogen- Glycogen Synthase
Glucose uptake (GLUT2 in the Liver/ GLUT4 in the Muscle)Formation of UDP-Glucose
Hydrolysis of PPi drives the reaction forwards
Glucose
Glucose-6-P
Hexokinase /GlucokinaseATP
ADP
Glucose-1-P
Phosphoglucomutase
PPi
UTP
UDP-Glucose
2Pi
Glycogen synthesis OR Glycogenesis
Glycogenin Tyrosine Glucose Glucose Glucose
Glycogen Fragment/Glycogenin to Initiate Glycogen synthesis
Glycogen synthesis OR Glycogenesis
UDP -Glucose UDP
Glycogen Synthase
Branching Enzyme
Glycogenin/Pre Existing Glycogen Fragment
Elongation- Glycogen Synthase
?
Summary of Glycogen Synthesis
NOT a reverse of Glycogenesis but a separate pathway
Site-Liver, Muscle Glycogen degradation requires the activity
of two enzymes
Glycogen PhosphorylaseDebranching enzyme
Glycogen Breakdown OR Glycogenolysis
Glycogen Phosphorylase Removes Glucose residues from the non
reducing end of Glycogen . It utilises the cytosolic phosphate for the
above process and releases glucose from glycogen as Glucose-1-PO4
The above process continues till 3-4 residues of Glucose remain from the branch point.
Debranching Enzyme Dual Enzyme activity[-(1 4) -(1 4) glucan transferase activity-
Transfers 3 glucose residues to the neighbouring branch to expose the branch point
[Amylo (1 6) transglucosidase activity breaks the branch point to release free Glucose.
90% of Glucose released from Glycogen as Glucose-1-PO4 and 10% as free Glucose
Rate limiting enzyme for Glycogen Degradation- Glycogen Phosphorylase
Glycogenolysis
Pi Glucose-1-PO4
GLYCOGEN PHOSPHORYLASE
DEBRANCHING ENZYME
DEBRANCHING ENZYME
GLUCOSE
Glycogenolysis
?
Allosteric regulation Glycogen Synthesis stimulated at high
levels of energy and substrateGlycogen Degradation increased when
energy and glucose supplies are low
Regulation of Glycogen Metabolism
MAJOR HORMONES IN METABOLISM
Liver
WATER SOLUBLE HORMONES IN METABOLISM
INSULIN-ANABOLIC HORMONE
GLUCAGON
INSULIN
Glycogen Phosphorylase
(Glycogen Breakdown)LESS ACTIVE
Glycogen Synthase(Glycogen synthesis)
ACTIVE
Glycogen Phosphorylase
(Glycogen Breakdown)ACTIVE
Glycogen Synthase(Glycogen synthesis)
LESS ACTIVE
GLUCAGON
INSULIN
GLYCOGEN SYNTHASE
GLYCOGEN PHOSPHORYLASE
INSULINLiver and Muscle
GLUCAGONLiver
GLUCAGONLiver
EPINEPHRINELiver and Muscle
Ca++ and AMPMuscle
INSULIN- Dephosphorylates key enzyme GLUCAGON/EPINEPHRINE- Phosphorylates key enzyme
Covalent Modification- Glycogen Metabolism
The muscle does not have receptors for
Glucagon
Covalent Modification- Glycogen Metabolism
Ca+2 by nerve stimulation (short bursts of exercise)
AMP as a result of rapid ATP consumption
Hormone independent Glycogen Phosphorylase activation in the
Muscle
Group of inherited disorders characterized by defective mobilization of NORMAL GLYCOGEN /Deposition of ABNORMAL GLYCOGEN
Classification based on the enzyme deficiency and affected tissue.
GSD can affect the liver, the muscles or both
About Eleven known types of GSD In general, GSDs - Autosomal-recessive
conditions EXCEPT, liver phosphorylase kinase deficiency (GSD IX).
Glycogen Storage Diseases Glycogen Storage Diseases (GSD)(GSD)
Patient History (Individual's symptoms) Physical Examination Biochemical tests (CK-Level). Occasionally, a muscle or liver biopsy
is required to confirm the actual enzyme defect.
GSD-DiagnosisGSD-Diagnosis
Primarily Liver involvement- I,IV,VI Primarily Muscle involvement- - II,V Both liver and muscle-III Adult onset-Mc Ardle’s(V) Most common, Clinically significant end-
organ GSD with significant morbidity-Type –I*
GSD with significant mortality-Type –II*
GSD-TYPES
Clinicopathologic Category
Specific Type Enzyme Deficiency
Hepatic TypeType I
Von Gierke disease Liver
Glucose-6-phosphatase
Generalized TypeType II
Pompe diseaseLiver, Skeletal and Cardiac
muscle
Lysosomal glucosidase (acid
maltase)
Myopathic TypeType V
McArdle SyndromeSkeletal muscle
Muscle phosphoylase
GSD-TYPES
•Hyperlipidemia
Children with GSD I are unable to release glucose from liver glycogen- “FASTING HYPOGLYCEMIA”
If untreated this results in prolonged periods when their blood sugar level is too low
They present in early childhood with
sweating, irritability, poor growth and muscle weakness
Liver enlargement -“HEPATOMEGALY” occurs due to excessive accumulation of Glucose-6-P AND glycogen (Cannot be broken down normally).
Primarily consists of giving glucose drinks frequently during the day and, in most cases, continuously overnight through a tube passed down the nose into the stomach (a nasogastric tube)
As children get older, treatment with cornstarch, which releases glucose slowly into the gut, may be very effective.
With such intensive treatment most children do well and their symptoms improve as they reach adulthood.
A 4-year old girl is brought to the hospital OPD with the complaints of sweating,headache,fatigue,nausea and loss of weight with symptoms more severe in the morning before breakfast. On Clinical examination , the child had hepatomegaly with severe fasting hypoglycemia.Further studies reveal inherited enzyme deficiency.Q1.What is your probable diagnosis ?
Q2. Which enzyme deficiency is responsible for the above clinical condition?
Q3. What is the cause of fasting hypoglycemia?
Some amount of glycogen is continuously degraded by the Lysosomal enzyme, acid maltase
Deficiency of the enzyme results in accumulation of glycogen vacuoles in the cytosol (liver, heart, muscle)
GSD II usually presents within the first months of life with severe muscle weakness and heart muscle involvement -“CARDIOMEGALY”.
No treatment has been found to prevent the progression of the most severe (infantile) form of this disorder
Affected children die from “HEART FAILURE ”, usually before the age of 18 months
There are however, milder forms of GSD II in which the heart is not affected and where symptoms do not develop until later in childhood or in adult life and the progression of the illness is slower
A 12 month old girl shows slowly progressing muscle weakness involving her arms and legs and developed difficulty in breathing .Liver was enlarged and CT scan revealed CARDIOMEGALY.A muscle biopsy showed muscle degeneration with many enlarged prominent Lysosome filled with clusters of electron dense granules. Her parents were told that without treatment ,the child’s symptom would continue to worsen and likely result in death in 1-2 year. Enzyme replacement therapy was initiated.
Q Which enzyme deficiency leads to the above condition?
Children with GSD III are often first diagnosed with a swollen abdomen due to a very large liver with large stores of normal glycogen
“Limit Dextrin” type of Glycogen (Glycogen structure with short outer branch and single glucose residue at alpha 1-6 of outer branch) deposit in the liver &muscle cells
Some children have problems with low blood sugars on fasting but this is not as common as in GSD I.
Treatment consists of a high protein diet and prevention of prolonged periods of fasting
Patients affected by this rare myopathy are unable to produce Glycogen phosphorylase, the enzyme involved in the cleavage of glycogen to glucose-1- phosphate and glucose during anaerobic exercise
The consequence is exercise-induced myalgia and fatigue
The disorder affects all skeletal muscle, which results in significant disability.
People with Mc Ardle's disease experience symptoms during anaerobic and sustained exercise.
These include fatigue and then pain occurring within a few minutes of exercise, which if continued, leads to muscle spasm known as a contracture.
Following severe exercise, muscle damage may occur leading to myoglobinuria. This is a dark discolouration of the urine and may be a warning sign for acute renal failure, which results from excessive muscle breakdown
A simple blood test will usually reveal raised levels of muscle creatine kinase (CK)
The diagnosis is confirmed by muscle biopsy, which shows an excess of glycogen and absence of muscle phosphorylase
In up to 85% of patients from Northern Europe, an abnormality in the gene encoding for muscle phosphorylase, called the R49X mutation, can be detected on a blood test
Regular aerobic exercise would increase the ability to switch to fat as the fuel source for the muscle
At the start of exercise, when pain occurs, exercise should be slowed down or stopped until the pain subsides (usually just for 30 seconds), then the exercise tried again
Continuing to exercise with intense pain would result in muscle damage and should be avoided.
A sensible diet, rich in protein, to help replace damaged muscle and avoiding excessive weight gain is important
Tourniquets should not be used during operative procedures
Affected women do not seem to be disadvantaged by pregnancy or childbirth. A normal childbirth is possible in women with McArdle's disease
A 35 year old man came to the hospital OPD with a history of limited capability to perform strenous exercise .Patient gave a history of muscle cramps and Myoglobinuria after strenuous exercise. Clinically patient was well developed and had no abnormality at rest. On investigation the patient was not hypoglycemic but ECG abnormalities were recorded.This condition is due to the deficiency in the activity of which enzyme?
Characterized by Mild Fasting Hypoglycemia with Hepatomegaly
Von Gierke’s v/s Her’s Disease Breakdown of Glycogen
Gluconeogenesis
Glucose-1-P
Glucose-6-P GLUCOSE