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Phosphorylase (parts of Chapter 15 Buchbinder et al. 2001)

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Metabolic pathway regulation through regulation of key enzymes (GP, in this case) ... The liver GP isozyme is normal, but the muscle one is not. ... – PowerPoint PPT presentation

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Title: Phosphorylase (parts of Chapter 15 Buchbinder et al. 2001)


1
  • Lecture 3
  • Phosphorylase (parts of Chapter 15 Buchbinder
    et al. 2001)
  • Discussion of paper and talk assignments.
  • Notes
  • A PDF of Buchbinder et al. 2001 will be posted
    on the course web site today. For your
    professional growth as a scientist (as well as
    potential extra credit on EXAM 1), you should
    read this paper.
  • The course materials will be posted on eRES
    soon, perhaps as early as this Friday.
  • The PASSWORD for this course on eRES will be
  • biochem2

2
Review Glycogenolysis requires 3 major
enzymes 1) GLYCOGEN PHOSPHORYLASE
(bond cleavage by phosphorolysis) Gl
ycogen(n units) Pi lt---gt Glycogen (n-1)
G-1-P inorganic
phosphate Glucose-1-phosphate 2)
GLYCOGEN DEBRANCHING ENZYME (Fig. 15-6) 3)
PHOSPHOGLUCOMUTASE (Fig. 15-7) G-1-P
lt---gt G-1,6-P lt---gt G-6-P

Glucose-1,6-bisphosphate
Glucose-6-phosphate G-6-P
has several fates (see Fig 15-1). In LIVER,
it is hydrolyzed to glucose Pi by
GLUCOSE-6-PHOSPHATASE.
3
Review Glycogen SYNTHESIS requires 3 major
enzymes, and occurs by a SEPARATE PATHWAY from
glycogenolysis 1) UDP-GLUCOSE
PYROPHOSPHORYLASE (Fig. 15-9) G-1-P UTP
lt---gt UDP-glucose (UDPG) PPi
Uridine triphosphate Uridine diphosphate
glucose inorganic
pyrophosphate 2) GLYCOGEN SYNTHASE
(Fig. 15-10) UDPG Glycogen(n units) lt---gt
UDP Glycogen(n1 units) This reaction must be
primed by GLYCOGENIN 3) GLYCOGEN BRANCHING
ENZYME (Fig. 15-11) or AMYLO (1,4--gt 1,6)
TRANSGLYCOSYLASE.

4
GLYCOGEN PHOSPHORYLASE (Review)
  • Is a FAST enzyme.
  • Is a dimer of identical 842-residue subunits.
  • Removes GLUCOSE UNITS from the NONREDUCING ends
    of GLYCOGEN.
  • Catalyzes the CONTROLLING STEP in glycogen
    breakdown.
  • Only releases units that are 5 or more from the
    branch (steric hindrance)
  • Is regulated by (Fig. 15-5 see Kinemages 14 on
    the CD with VVP)
  • ALLOSTERIC INTERACTIONS
  • ATP, G6P glucose inhibit it
  • AMP activates it.
  • COVALENT MODIFICATION
  • phosphorylation at Ser-14 (Phosphorylase
    A)more active
  • dephosphorylation (Phosphorylase B )less
    active

5
  • Glycogen phosphorylase is a model for
    understanding many general principals in
    biochemistry, including
  • The basis of metabolic pathway regulation
    through
  • regulation of key enzymes
  • The 3D structural basis of enzyme regulation
  • Evolution of regulatory mechanisms
  • Gene duplication and divergence of the
    isozymes
  • Tissue-specific regulation of isozymes
  • The structural basis of inherited biochemical
    disorders
  • (such as McArdles disease see Box 15-2)

6
Gene duplication and divergence is extremely
common during evolutionary history
Gene copy 1
Gene copy 2
The resulting gene duplicates are often expressed
in different tissues as different isozymes with
somewhat different structures and functions.
7
Metabolic pathway regulation through regulation
of key enzymes (GP, in this case)
Mammals have liver- and muscle-specific isozymes
of GP
Fig. 15-12
8
3,5-Cyclic AMP (cAMP) synthesis and breakdown
9
Control of GP activity
Most active R form
Fig. 15-13
10
  • Glycogen Storage Diseases (Box 15-2)
  • Type V
  • Muscle Phosphorylase Deficiency (McArdles
    Disease)
  • Inherited (genetic) disease
  • Causes painful muscle cramps upon exertion
  • Usually does not appear until early adulthood
  • Glycogen metabolism in muscle is hindered, so
    that the
  • muscles cant get enough fuel for glycolysis
  • Liver glycogen metabolism is normal
  • HOW could this be?

11
  • Glycogen Storage Diseases (Box 15-2)
  • Type V
  • Muscle Phosphorylase Deficiency (McArdles
    Disease)
  • Inherited (genetic) disease
  • Causes painful muscle cramps upon exertion
  • Usually does not appear until early adulthood
  • Glycogen metabolism in muscle is hindered, so
    that the
  • muscles cant get enough fuel for glycolysis
  • Liver glycogen metabolism is normal
  • HOW could this be?

The liver GP isozyme is normal, but the muscle
one is not. (There are several different
mutations that can cause McArdles Disease.)
12
Fig. 15-3a 3D structure of GP
See Kinemage Exercise and Buchbinder et al. now..
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