Metabolic Biochemistry

BIBC102
Lecture 12
October 23, 2013
 From Strange Simplicity to
Complex Familiarity: A Treatise
on Matter, Information, Life, and
Thought
by Manfred Eigen
Oxford University Press, Oxford, 2013.
754 pp. $225, £125. ISBN
Ernst Haeckel's depiction of the radiolarian
Sagenoscena stellata

(protozoa of (diameter 0.1–0.2 mm) that produce

intricate mineral skeletons)
Glycogen Breakdown

4 Pyridoxal phosphate
cofactor
Glycogen Synthesis
Distinction between :

1) Chain Initiation

2) Chain Elongation (previous slide)

3) Branching
each glycogen molecule has many
non-reducing ends
A highly branched glycogen molecule:

- a relatively large amount of glucose can be stored in a cell

without perturbing the osmotic pressure in the cell

- has a very compact structure (contains one glycogenin at its center)

- has many non-reducing ends

- glycogen phosphorylases can “attack” many ends simultaneously

and therefore the release of Glu 1-P is greatly increased
when needed for glycolysis and ATP production
 The balance between glycogen degradation and synthesis
is carefully controlled

Glucose concentrations in the blood are maintained constant

within narrow limits
 GLYCOGEN

synthase phosphorylase

UDP-Glu Glu-1P

Glu-6P

Glu
Fru-6P

Fructose-1,6-bis
phosphatase Phosphofructokinase
Fru-1,6 bis P (PFK-1)

DHAP + GAP
 GLYCOGEN

synthase
phosphorylase
UDP-Glu Glu-1P

Glu-6P

Fru-6P

Fructose-1,6-bis Phosphofructokinase
phosphatase (PFK-1)
Fru-1,6 bis P

DHAP + GAP
 Glycogen Phosphorylase Regulation
• The enzyme is a dimer
• It has several allosteric effectors/modulators:
AMP, ATP, glucose, Glu 6-P
• It can be covalently modified by
phosphorylation at a critical serine side chain
PROTEIN PHOSPHORYLATION
A MECHANISM TO CONTROL
ACTIVITY
 Control of glycogen phosphorylase activity

Covalent modifications
least active

Ligand-induced
conformational
changes spontaneous

phosphatase

most active
b

a
GLUCOSE IS A LIGAND
ACTING AS A NEGATIVE
MODULATOR
 Two new enzymes for covalent
modification of proteins*

• Phosphorylase b kinase

• Phosphorylase a phosphatase

* - also known as post-translational modificationss

These kinases and phosphatases are themselves subject to
regulation by small molecules (ligands)

Two of these ligands are so ubiquitous and versatile that

they are also referred to as “second messengers”:

cAMP and cGMP

 cAMP is a “second messenger” in cells

adenyl
cyclase

ATP cAMP

phosphodiesterase
ADP

AMP
The concentration of cAMP at any time is controlled by the activities of the
cyclase and the diesterase

adenyl cyclase

ATP cAMP

phosphodiesterase
ADP
AMP
cAMP-dependent Protein Kinase
cGMP is another
“second messenger” in cells

guanyl
cyclase

GTP cGMP

phosphodiesterase

GMP
A SIGNAL TRANSDUCTION PATHWAY
 hormone

Glycogen  Glu 1-P

 muscle liver

G-protein-coupled
receptor mechanism

epinephrine = adrenaline

stimulates glycogen
breakdown and
glycolysis
 SIGNAL TRANSDUCTION:

- an extracellular signal is converted into an intra-cellular signal for activation or

inactivation of one or more target enzymes

- in the process each intermediate protein (e.g. kinase) acts as an amplifier

- the end result is a large signal amplification

- signal transduction pathways can be branched

 S T U V W
E5 A

B
HORMONE  E1 cAMP E2 E3 E4

E
E6
M N O P Q R
F

A signal transduction pathway

Three pathways controlled by a single hormone
End of Lecture 12

October 23, 2013