METABOLISM OVERVIEW
Student Edition
5/24/13 Version
Dr. Brad Chazotte
213 Maddox Hall
chazotte@campbell.edu
Web Site:
http://www.campbell.edu/faculty/chazotte
Original material only ©2000-14 B. Chazotte
Pharm. 304
Biochemistry
Fall 2014
Goals
•
•
•
•
Understand that there is a chemical “logic” to metabolism.
Understand the thermodynamic logic of metabolism.
Understand the role of coupled reactions in metabolism
Understand how various mammalian organs interact metabolically
in the flow of energy (fuels).
• Learn the various types of chemical reactions in metabolism.
• Remember metabolically important electrophiles & nucleophiles.
• Learn the principal ways metabolic processes are regulated
METABOLISM:
•Metabolism comprises the entire network of chemical reactions in living
cells.
•Bioenergetics and metabolism are closely inter-related.
•Intermediary metabolism is a term applied to reactions involving low
molecular weight molecules. These metabolites are the small molecules
that are the intermediates in biopolymer synthesis or degradation.
•Reactions that degrade molecules to liberate smaller molecules and
energy are called catabolic reactions.
•Reactions that synthesize molecules that the cell uses for growth
reproduction and maintenance are called anabolic reactions. These
reactions require energy.
Topic: Metabolism Horton et al., 2002 3 rd p309
Living organisms require a continual input
of energy for three major purposes:
1. Performance of mechanical work in muscle contraction and other
cellular movements.
2. Active transport of molecules and ions.
3. Synthesis of macromolecules and other biomolecules from
simple precursors
Living organisms derive energy from the
environment to maintain the organism in a
thermodynamic state far from equilibrium
Metabolic (Logic) Principles
•Metabolic Pathways are irreversible
The existence of independent interconversion routes is an important property of
metabolic pathways because it allows independent control of rates of the two processes.
•Every metabolic pathway has a first committed step.
However, most of the component reactions are at or near equilibrium.
•All metabolic pathways are regulated.
Most metabolic pathways are controlled by regulating the enzymes that catalyze
their first committed steps.
•Metabolic pathways in eukaryotic cells occur in specific cellular
locations.
The synthesis of metabolites in specific membranebounded subcellular compartments makes their transport
between these compartments a vital part of eukaryotic
metabolism.
Voet ,Voet, & Pratt 2013 p.444
Voet ,Voet, & Pratt 2013 Fig. 14.4
COMMON THEMES FOR ORGANISMS
IN METABOLISM:
•Cell membranes provide the physical barriers that form compartments and
segregation from the external environment.
•Specific internal conc. of inorganic ions, metabolites & enzymes are maintained.
•Energy for Rx is extracted from external sources either by photosynthetic reactions or
solely chemically from the ingestion & catabolism of energy-containing molecules.
•Metabolic pathways in each organism are specified by its genes.
•Interaction with the environment: activities of cells are geared to the availability of
energy. Growth & reproduction occur in energy-rich environments. In energy-poor
environments organism can temporarily reduce demand by slowing metabolic rates or
use internals stores. Eventually they may die.
•Cells are dynamic. Many components are continually synthesized and degraded
(turnover) while their concentrations are essentially static. Topic: Metabolism Horton et al., 2002 3 p311-312
rd
TROPHIC STRATEGIES I:
The nutritional requirements of an organism are a reflection of its metabolic
free energy source.
Autotrophs: synthesize all their cellular constituents from simple
molecules: e.g. H2O, CO2, NH3 and H2S. - some prokaryotic organisms
Chemolithotrophs: obtain their free energy via the oxidation of inorganic
compounds, e.g. NH3, H2S, and Fe2+.
Photoautotrophs: obtain their free energy via photosynthesis – light energy
to produce carbohydrates from CO2.
Heterotrophs: obtain free energy via the oxidation of organic compounds,
e.g. carbohydrates, lipids, proteins.
Topic: Metabolism Voet, Voet & Pratt, 2013 p437
TROPHIC STRATEGIES II:
Additional classification based on the oxidizing agent for nutrient
breakdown.
Obligate Aerobes: must use O2,
- includes animals
Aerobes: employ sulfate or nitrate as oxidizing agents.
Facultative anaerobes: can grow either in the presence of absence of O2.
Example: E. Coli.
Obligate Anaerobes: grow in the absence of O2 and are in fact poisoned by
oxygen.
Topic: Metabolism Voet, Voet & Pratt, 2013 p437
Nutrients, Organs, and Circulation
IN GENERAL:
An organ
specialized to
produce a certain
fuel lacks the
enzymes to use
that fuel.
Major fuel depots are:
Triacylglycerolsstored mainly in
adipose tissue
Protein –most of it
existing in skeletal
muscles
Glycogen – which is
stored primarily in liver
and muscle
Matthews et al 2003 Fig 23.1
Major Events: Storage, Retrieval, & Use of “Fuels”
Matthews et al 2003 Fig 23.4
Metabolism and Thermodynamic
Logic
Metabolism in some ways is concerned with the liberation
of energy from molecules in order to do work, drive other
reactions, or to help synthesize other molecules.
THERMODYNAMICS
FREE ENERGY
At constant temperature and pressure
DGp,T = DH -TDS
The free energy change can be defined as that portion of the total energy change
which is available to do work as the system proceeds to equilibrium at constant
temperature and pressure.
The conditions of constant temperature and pressure are typical of biological systems.
One can also state that for a reaction that :
DGreaction = DG products -  DGreactants
Cramer & Knaff 1990
THERMODYNAMICS: Free Energy 1
Free Energy Change of Chemical Reactions:
Consider the relationship between a chemical reaction and its equilibrium constant.
reactants  products
aA + bB 
cC + dD
Where a,b,c,d, are the number of molecules of A,B,C and D in the reaction. The free
energy change at constant temperature and pressure is given by:
[C]c [D]d
DG
=
DG + RT ln [A]a [B]b
[ ] = molal concentrations
R = gas constant = 1.98 cal-1 mol-1 = 8.315 joules mole-1 deg-1
T = abs. Temp in  K
DG is the standard free energy change of the reaction, here defined as at 298 ºK, at
component concentrations of 1 M and 1.0 atm. pressure.
Cramer & Knaff 1990; Lehninger 1977
Coupled Reactions in
Metabolism
Metabolism, at its most fundamental, is basically a series of linked
chemical reactions that take one molecule and convert it to another
molecule or molecules in a carefully defined fashion.
Glucose
Metabolism
Metabolism Overview
Berg, Tymoczko & Stryer, 2012 Fig. 15.1
Chart of
Metabolic
Pathways
Berg, Tymoczko & Stryer, 2012 Fig. 15.2
Prominent Fuels
Metabolism Overview
Berg, Tymoczko & Stryer, 2012 Fig. 15.10
Complete Oxidation to Molecular Oxygen
Glucose
C6H12O6 + 6 O2
Note: 1 cal =4.184J
6 CO2 + 6 H2O
D G° ’=-2823 kJ mole-1
Broken down into the half reactions:
C6H12O6 + 6 H2O
6 O2 + + 24H+ + 24 e-
6CO2 + 24H+ + 24 e12 H2O
Palmitic Acid
Palmitoyl-CoA + 23O2 + 131 Pi + 131 ADP
ATP
Palmitic Acid + 23 O2
129 ADP + 129Pi
CoA + 16CO2 + 146 H2O +131
16 CO2 + 16 H2O
D G°’= -9790.5 kJ mole-1
129 ATP + 129 H2O
D G°’= +3941 kJ mole-1
129 ATP is the next yield since 2 ATP are needed to form palmitoyl-CoA from
palmitic acid. To Form 1 ATP D G°’= +30.54 kJ mole-1 = 7.3 kcal mole-1
Stages of
Catabolism
Metabolism Overview
Berg, Tymoczko & Stryer, 2012 Fig. 15.12
Reoccurring “Motifs” in Metabolic
Pathways
Modular Design & Economy:
Activated Carriers
Economy of Metabolic Design:
Six Reaction Types
Design of Metabolic Regulation:
Three Control Mechanisms
Berg, Tymoczko & Stryer, 2002 Glycolysis
Example of Metabolic Activated Carriers
Metabolism Overview
Berg, Tymoczko & Stryer, 2012 Table. 15.2
Common Vitamin and Their
Characteristics
Voet, Voet & Pratt 2013 Table 14.1
Berg, Tymoczko & Stryer, 2012 Table. 15.3, 15.4
CHEMICAL LOGIC IN METABOLISM
and the Economy of Metabolic Design
Types of Metabolic Chemical Reactions
Metabolism Overview
Berg, Tymoczko & Stryer, 2012 Table. 15.5
Modes of C-H Bond Breaking
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig 15.4
Compound Types In Heterolytic Bond
Cleavage
Breaking a covalent bond where the electron pair of the covalent bonds remains
with one of the atoms. (Homolytic:electron pair split between atoms.)
NUCLEOPHILES (“nucleus lovers”) – Electron-rich compounds
that are negatively charged or contain unshared electron pairs that easily form
covalent bonds with electron-deficient centers. Important groups: amino,
hydroxyl, imidazole, and sulfhydral groups.
ELECTROPHILES (“electon lovers”)– Electron deficient
compounds that can be positively-charged, contain an unfilled valence electron
shell, or contain an electronegative atom. Most common biological ones are:
H+, metal ions, the carbon atoms of carbonyl groups and cationic imines.
Metabolism: Chemical Logic
Voet & Voet 1995, p416
Biologically Important Nucleophilic Groups
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig. 15.5
Nucleophilicity and Basicity are Closely
Related Properties
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Chap 15 Fig. p416
Biologically Important Electrophiles
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig. 15.6
Group Transfer Reactions
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Chap 15 Fig. p417
Types of Metabolic Group Transfer Reactions
nucleophile
Orig. acyl
carrier
Acyl group transfer
carbonyl
carbon
nucleophile
Phosphoryl group
transfer
Apical leaving
group
Apical
attacking group
Glycosyl group
transfer
C1 carbon
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig. 15.7
Oxidation-Reduction Rx’s
Metabolism: Chemical Logic
Possible Elimination Reactions Mechanisms
(e.g., dehydration reaction)
Note: Elimination
reactions result in the
formation of a double
bond between two
previously singlebonded, saturated
centers.
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig. 15.9
ALDOSE-KETOSE ISOMERIZATION
MECHANISM
Biochemical
isomerizations
involve the
intramolecular
shift of a
hydrogen atom
to change the
location of a
double bond.
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig 15.10
Examples of C-C Bond Formation and
Cleavage Reactions
Reactions that make
and break C-C bonds
forms the basis of both
degradative and
biosynthetic
metabolism
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig 15.11
Stabilization of Carbanions
Metabolism: Chemical Logic
Voet & Voet Biochemistry 1995 Fig. 15.12
Regulation of Metabolic Processes
Principal Ways
•The amount of enzymes
•The catalytic activities of the enzymes
•The accessibility of substrates
Metabolism Overview
Berg, Tymoczko & Stryer, 2002 Metabolism Overview
Control of the amount of enzyme
The amount of a particular enzyme depends on both its
rate of synthesis (genetic control) and its degradation.
For most enzymes their level is primarily controlled by
altering the rate of transcription of their genes. (In higher
organism the response is on the order of hours or days.)
Example: Lac operon in E. Coli (lower organism) – in the
the presence of lactose a 50-fold increase in the synthesis of
-galactosidase occurs within minutes of exposure.
Metabolism Overview
Berg, Tymoczko & Stryer, 2002 Metabolism Overview
Control of enzyme catalytic activity
•Reversible allosteric control
Allosteric effectors are often substrates, products or coenzymes. Consider that
the first reaction of many biosynthetic pathways is inhibited by the ultimate product –
for instance, cytidine triphosphate inhibits the enzyme aspartate transcarbamylase, an
example of feedback inhibition which can be nearly instantaneous
•Reversible covalent modification
Typically phosphorylation or dephosphorylation is used. For instance,
glycogen phosphorylase is activated by the phosphorylation of a specific serine residue
at low glucose levels. Covalent modification may, in turn, be controlled by hormones.
•Hormones coordinate metabolic relations between different tissues.
This is frequently accomplished by regulating the reversible modification of
key enzymes. For instance, epinephrine effect on muscle tissue or insulin promoting
the uptake of glucose into many kinds of cells
Metabolism Overview
Berg, Tymoczko & Stryer, 2002 Metabolism Overview
Control of substrate flux
Regulation of the movement of substrates from one
compartment to another can serve as a control point.
For instance, the movement of long-chain fatty acids from
the cytosol to the mitochondrial matrix.
Metabolism Overview
Berg, Tymoczko & Stryer, 2002 Metabolism Overview
End of Lecture
Metabolism Overview
Berg, Tymoczko & Stryer, 2002 Metabolism Overview