Regulation of metabolic pathways at whole cell level. It encloses basic understanding of use and the need for regulation. Emphasis is given on glycogen metabolism and the changes a cell undergoes in fed and fasting state. Regulation of various metabolic pathways make sure the cell survives in a particular condition.

1. Metabolic Regulation at Whole
Cell Level
Presented by:
Sakshi Agrawal
MSc. Biotechnology
Roll no 191515
Central University of

2. Introduction
Metabolic regulation is a term used to describe the process by which metabolic pathways
(both the anabolic/biosynthetic and catabolic/ degradative pathways) are regulated .
Of the thousands of enzyme-catalyzed reactions that can take place in a cell, there is
probably not one that escapes some form of regulation.
The ability of a cell to carry out all these interlocking metabolic processes simultaneously
obtaining every product in the amount needed and at the right time.
Glucose-6-
Phosphate
Synthesis of other
sugars Protein Glycosylation
Partially degraded to
provide acetyl CoA for
fatty acid metabolism
E.coli uses as
carbon skeleton

3. Source:
www.genome.ad.jp/kegg/pathway/map/map01100.html
A typical eukaryotic cell has the
capacity to make about 30,000
different proteins, which catalyze
thousands of different reactions
involving many hundreds of
metabolites, most shared by more
than one “pathway.”

4. Difference between regulation at whole cell level and metabolic level?
•A whole cell regulation
depicts the net change in the
metabolic flux due to external
changes encountered by a
cell.
•It is the net result of
individual metabolic
reactions.
Regulation at metabolic level
specifically accounts individual
reactions that leads to overall
metabolism or condition of a
cell.

5. Regulation of Glycogen
• Glycogen granules are complex aggregate of glycogen and enzymes that synthesize
and degrade it.
• The general mechanism for storing and mobilizing glycogen are same in Liver and
Muscle.
• But enzymes differ due to different roles in both tissues.
• In gut; Glycogen is converted to free glucose (Diff. set of enzymes).
•Glucose 1-phosphate, the end product of the glycogen phosphorylase reaction, is
converted to glucose 6-phosphate by phosphoglucomutase.
Fig: Glycogen granules in
Hepatocytes.
Source: Nelson, D. L., & Cox, M. M. (2017). Lehninger principles of biochemistry (7th ed.). W.H. Freeman.

6. LIVER
SKELETAL
MUSCLE
•Release glucose into blood when the
blood glucose level drops.
•Glucose-6-phophatase (+ only
in liver & kidney)
•Serve as energy source to support
muscle contraction.
•Lack Glucose-6-phosphatase so;
don’t contribute to blood glucose.

7. Pathways
Catabolic
Glycogenolysis Glycolysis
Anabolic
Gluconeogenesis Glycogenesis
Glycogen to Glucose-6-phosphate
Glucose-6-phosphate to Pyruvate
Pyruvate to Glucose
Glucose to Glycogen

8. Mechanisms for Regulation of Key Enzymes
•Appropriate adjustments are made in the rate of metabolite flow through the
whole pathway if external circumstances change.
•The demand for ATP production in muscle may increase 100-fold in a few seconds
in response to exercise
•Relative proportions of carbohydrate, fat, and protein in the diet vary from meal
to meal, requiring metabolic adjustments between meals and during starvation
•Wound healing requires huge amounts of energy and biosynthetic precursors.

9. Living Cells Maintain a Dynamic Steady State
• Mass and gross composition of a typical cell don’t change over time.
• Cells exist in a dynamic steady state; but not at equilibrium with their surrounding.
• Rate of metabolite flow (Flux) through the pathway may be high but concentration of
substrate remains constant.
• When steady state is disturbed by some external changes,
temporarily fluxes are alteresd through individual metabolic
pathway.
•Trigger regulatory mechanism intrinsic to each pathway.
•The net effect of all these adjustments is to return the organism to a
new steady state. (Homeostasis)

10. Regulatory Mechanisms Evolved under Strong
Selective Pressures
4000
genes
Regulatory
proteins
• Receptors
• Regulators of gene expression
• 500 different protein kinases
• Regulatory mechanism act over different time scales and have different sensitivities to
external changes.
•The mechanism overlap; one enzyme is subject to regulation by different mechanism.

11. ATP is very
important
ATP using enzymes have Km between 0.1 to 1mM.
ATP concentration in typical cell = 5mM
If [ATP] drop significantly – rate of hundred of reaction
that involve ATP would decrease and cell would not
survive.
Brain has no
stored form of
energy
Glucose drops from 4-5mM (half) causes
Mental Confusion
5 fold decrease leads to Coma and death

12. Regulation of Glycolysis and Gluconeogenesis:
•Gluconeogenesis is performed primarily in Liver.
•Glucose for export to other tissues.
The reaction of glycolysis are so exergonic as to be essentially reversible
-Hexokinase
- PFK-1
- Pyruvate kinase
Large negative ΔG’
Simultaneous operation of both pathways would consume ATP without
accomplishing any chemical or biological work.

13. Fig: Glycolysis and gluconeogenesis
Source: Nelson, D. L., & Cox, M. M. (2017). Lehninger principles of biochemistry (7th ed.). W.H. Freeman.

14. Different isoenzymes of liver and muscle:
LIVER MUSCLE
Blood glucose homeostasis by
removing or producing glucose.
Consumes glucose
HEXOKINASE IV
HEXOKINASE I-III

15. • High Km of hexokinase IV allows
direct regulation by the level of blood
glucose.
•When blood glucose is increased
(after meal) ,
- excess glucose is transported to
hepatocytes.
• Hexokinase IV convert to glucose-6-
phosphate.
•It is not saturated at 10mM
(continues activity)
1
Fig: Comparison of the kinetic properties
of hexokinase IV (glucokinase) and
hexokinase I.
Source: Nelson, D. L., & Cox, M. M. (2017). Lehninger principles of biochemistry (7th ed.). W.H. Freeman.

16. • Inhibition by reversal binding of Regulatory protein specific to liver.
• Fructose-6-phosphate act as Allosteric Effector
• Glucose-6-phosphate competes with Fructose-6-phosphate.
•Regulatory protein anchors Hexokinase IV inside the nucleus.
Glucose
increase
Equillibriate
through NPC
Cause
dissociation of
regulatory
protein
Hexokinase IV
release to
cytosol
Fig: Regulation of hexokinaseIV (glucokinase) by sequestration in the nucleus.
2
Source: Nelson, D. L., & Cox, M. M.
(2017). Lehninger principles of
biochemistry (7th ed.). W.H. Freeman.

17. • Hexokinase IV
• Not inhibitted by glucose-6-phosphate
• Continue to operate at high concentrationn of
glucose-6-phospahte
• Completely inhibits Hexokinase I-III
3

18. Source: https://www.crossfit.com/wp-content/uploads/2020/05/28092926/Fed-vs-Fasted-State.jpg
Effect of feeding and fasting on metabolism

19. Regulation of insulin and glucagon secretion
Source: https://www.endocrineweb.com/images/sugar.gif
Glucagon signals
increase
 Mobilization of
stored fuels:
-Glycogen (Liver)
- TAG (Adipose tissue)
- Protein (Skeletal
muscle)
Increase availability
of circulating fuels
Increase level of
insulin
Anabolic
metabolism
Fasting Fed state

20. References:
•Nelson, D. L., & Cox, M. M. (2017). Lehninger principles of biochemistry (7th
ed.). W.H. Freeman.
•Agius,L., 2008. Glucokinase and molecular aspects of liver glycogen metabolism.
Review article.BiochemicalJournal414,1–18.