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Glycogen Metabolism - Medscistudents

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					              Glycogen metabolism
· It is the storage from of glucose in animals
· Stored in liver (6-8%) and muscle (1-2%)
  Helps to maintain the blood glucose levels,between
  meals
  Glycogen stores increase in a well-fed state depleted
  during fasting
· Muscle glycogen serves as a fuel reserve for the
  supply of ATP during muscle contraction
  In homopolysaccharide, glucose molecules held
  together by - 1,4 linkages. Branch with -1, 6 linkage.
  Glucokinase in liver and hexokinase in muscle which
  converts glucose to glucose–6 phosphate



                          DR S Nayak                   1
              Glycogenesis

Synthesis of glycogen from glucose
Occurs in liver and muscle
Storage from in liver and muscle
After the meal excess glucose is converted into
glycogen
UDPG is the carrier of glucose
Glucose from UDPG is attached at the non-reducing
end of glucose molecules of glycogen primer

                    DR S Nayak                2
              ATP ADP          Phosphoglucomutase
 Glucose                Glu –6-P                Glu-1-P
              Hexokinase
              Glucokinase          UDPG pyrophosphorylase
                                         UTP
                                         PPi
                        Uridine diphosphate glucose (UDPG)
                                           Glycogen synthase
                          Glycogen primer            UDP

  Glycogen                                  (1, 4 glucosyl units) n
(1, 4 and 1,6      Branching enzyme
Glucosyl units) n (Amylo-1, 4-1,6- transglucosidase)
                      (Glucosyl -4,6 transferase)


                             DR S Nayak                        3
Glycogenesis




   DR S Nayak   4
   It is found that in the absence of glycogen primer,
    a specific protein,GLYCOGENIN can accept glucose
    from UDPG. The initial glucose is attached to the
    OH group of tyrosine residue of glycogenin.
    The enzyme glycogen initiator synthase
    transfers the first molecule of glucose to glycogenin.
    Later glycogenin itself takes up a few glucose
    residues to form a fragment of primer

 Branching enzyme (Amylo 1,4 –1,6 transglucosidase
  transfers 6 glucose residues portion from one chain
  to a neighbouring chain to form a -1,6 – linkage
                          DR S Nayak                  5
             Glycogenolysis
 Breakdown of glycogen to glucose
·Occurs in liver and muscle
·End product of liver glycogenolysis is glucose
·Muscle glycogenolysis is lactate (strenuous exercise)
 Muscle and brain does not contain glu-6-phosphatase

            Phosphorylase       Pi
Glycogen                        Glu-1-P
               Phosphoglucomutase
                                Glu –6-P
              Glu-6-Phosphatase       H2O
                                      Pi
                                  Glucose


                       DR S Nayak                   6
 Phosphorylase phosphorolytically splits -1,4
  glucoside bonds from the outermost chains of
  glycogen until 4 residues remain on either side of
  – 1.6 branch point [limit dextrin]
  1.4 glucan transferase transfers 3 glucose
   residue portion from one side chain to the other
   exposing -1,6 branch points
 Amylo 1, 6 glucosidase splits the 1,6 linkages

 Acid maltase or -1,4-glucosidase (lysosomal enzyme)
  degrades small quantity of glycogen. The significance of this
   pathway is not clear


v           Muscle glycogenolysis
Glycogen  Glu-1-P  Glu-6-P   glycolysis  lactate
                             DR S Nayak                       7
Glycogenolysis




    DR S Nayak   8
   Regulation of glycogenesis and glycogenolysis

· The glycogen synthase and phosphorylase exist in
  active and inactive forms
· The dephosphorylated form of glycogen synthase is
  active
· Phosphorylated form of phosphorylase is active
  The activation of phosphorylase depends on high
   cAMP level. At the same time high cAMP level
   inactivates glycogen synthase

  Glycogen synthase b        Phosphorylase a
  H2O         Protein phosphatase
  Pi
  Glycogen synthase a        Phosphorylase b
  (Glycogenesis ON)       (Glycogenolysis OFF)
                      DR S Nayak                   9
               Allosteric regulation
    In a well fed state Glu–6– P level is high which
    activates glycogen synthase
·   On the other hand glu-6-p and ATP allosterically
    inhibit phosphorylase
·   Free glucose also act as inhibitor to phosphorylase

    Glucose –6 –P ATP Liver glucose Muscle AMP
           _      _        _
           Glycogen Phosphorylase +       Ca2+
    Glycogen                  Glu-1-Phosphate
              Glycogen Synthase

                   +
             Glucose-6-phosphate

                         DR S Nayak                  10
                  Adrenaline (Liver and muscle)
                  Glucagon + (Liver only)
Adenylate Cyclase                Adenylate Cyclase

             ATP           cAMP
                     PPi
Protein Kinase                 Protein Kinase
           ATP ADP                            ATP ADP
Phosphorylase       Phosphorylase Glycogen          Glycogen
Kinase              kinase           Synthase (a)  synthase (b)
Phosphorylase (b)        Phosphorylase (a)
               2ATP   2ADP
           Glycogen            Glucose-1-P
                        Pi

cAMP             51 AMP           Glycogenesis ON
   + Phosphodiesterase
Insulin                     DR S Nayak                   11
                GLYCOGEN STORAGE DISEASES
Genetic diseases [may be inherited]
Deposition of abnormal type or quantity of glycogen in the tissues
Diseases                       Defect and Features
Type I.                       Glucose – 6 – phosphatase [liver]
Von Gierke’s disease          Accumulation of glycogen in liver
                              Hypoglycaemia and ketosis
Type II.                      Lysosomal -1, 4 – glucosidase
Pompe’s disease               Glycogen accumulates in
                              lysosomes, in all tissues
                              Enlarged liver and heart
Type III.                     Debranching enzyme [amylo -1,6-
Limit dextrinosis             glucosidase
[Coris disease]               Accumulation of polysaccharide
                              [limit dextrin] liver, heart, & muscle
TypeIV. Amylo pectinosis or Branching enzyme (glucosyl 4-6 transferase)
Andersons disease             Accumulation of polysaccharide with few
                              branch points. Cirrhosis of liver
                                 DR S Nayak                          12
Type V                         Muscle glycogen phosphorylase
McArdles disease               Glycogen accumulates in the muscle
                               Diminished tolerance to exercise
Type VI.                       Liver glycogen Phosphorylase
Hers disease                   Liver enlarged
                Von Gierke’s Disease
1. Fasting hypoglycemia
2. Lactic acidemia:Glucose is not synthesized from lactate produced in
   muscle and liver. Lactate level increases and pH decreases
3. Hyperlipidemia: Block in gluconeogenesis leads to mobilisation fat to
   meet energy requirement. So This increases free plasma FA & ketone
   bodies.
4. Hyperuricemia: Accumulated glucose -6-p diverted to HMP pathway,
   leading to increased synthesis of ribose and nucleotides, this enhances
   metabolism of purine nucleotides and to uric acid later
5. Massive liver enlargement leads to cirrhosis
6. Children fail to grow
                                    frequent
   Given small quantity of food atDR S Nayak intervals              13
DR S Nayak   14

				
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posted:8/8/2012
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