Chap 10 Introduction to

Metabolism
QUIM 4050
Migdalia Chevres, Ph.D.
Department of Chemistry
UPRB
•  Metabolism is the entire network of chemical
reactions carried out by living cells.
•  Metabolites are the small molecules that are
intermediates in the degradation or
biosynthesis of biopolymers.
•  Anabolic reactions are those responsible
for the synthesis of all compounds needed
for cell maintenance, growth, and
reproduction.
•  These biosynthesis reactions make simple
metabolites such as amino acids,
carbohydrates, coenzymes, nucleotides, and
fatty acids.
•  They also produce larger molecules such as
proteins, polysaccharides, nucleic acids, and
complex lipids.
NADH, NADPH, and FADH2 (Fig. 3). zymes, operating in one direction for anabolism, the oppo-
Some metabolic pathways are linear, and some are site direction for catabolism: inhibition of an enzyme
branched, yielding multiple useful end products from a involved in catabolism would also inhibit the reaction se-
single precursor or converting several starting materials quence in the anabolic direction. Catabolic and anabolic
into a single product. In general, catabolic pathways are pathways that connect the same two end points (glucose
convergent and anabolic pathways divergent (Fig. 4). n n pyruvate, and pyruvate n n glucose, for example)
Some pathways are cyclic: one starting component of may employ many of the same enzymes, but invariably at
least one of the steps is catalyzed by different enzymes in
the catabolic and anabolic directions, and these enzymes
Cell Energy- are the sites of separate regulation. Moreover, for both an-
macromolecules containing
nutrients
•  Catabolic reactions degrade
abolic and catabolic pathways to be essentially irre-
Proteins
Polysaccharides
Lipids
Carbohydrates
Fats
large molecules to liberate
versible, the reactions unique to each direction must
include at least one that is thermodynamically very favor-
Nucleic acids Proteins
smaller molecules and energy.
able—in other words, a reaction for which the reverse re-
action is very unfavorable. As a further contribution to the
•  All cells carry out degradation
separate regulation of catabolic and anabolic reaction se-
quences, paired catabolic and anabolic pathways com-
ADP ! HPO2"
NAD!
4 reactions as part of their normal
monly take place in different cellular compartments: for
NADP
cell metabolism but some
!
example, fatty acid catabolism in mitochondria, fatty acid
FAD
synthesis in the cytosol. The concentrations of intermedi-
Anabolism ATP Catabolism species rely on them as their
ates, enzymes, and regulators can be maintained at differ-
ent levels in these different compartments. Because
NADH
NADPH
FADH2
only source of energy.
metabolic pathways are subject to kinetic control by sub-
strate concentration, separate pools of anabolic and cata-
•  Amphibolic reactions. They are
bolic intermediates also contribute to the control of
Chemical
energy involved in both anabolic and
metabolic rates. Devices that separate anabolic and cata-
bolic processes will be of particular interest in our discus-
catabolic pathways.
sions of metabolism.
Precursor Energy- Metabolic pathways are regulated at several levels,
molecules depleted
end products
from within the cell and from outside. The most immedi-
Amino acids
Sugars CO2
ate regulation is by the availability of substrate; when the
Fatty acids H2O intracellular concentration of an enzyme’s substrate is
Nitrogenous bases NH3
near or below Km (as is commonly the case), the rate of
the reaction depends strongly upon substrate concentra-
FIGURE 3 Energy relationships between catabolic and anabolic path- tion (see Fig. 6–11). A second type of rapid control from
ways. Catabolic pathways deliver chemical energy in the form of ATP,
within is allosteric regulation (p. 220) by a metabolic in-
NADH, NADPH, and FADH2. These energy carriers are used in ana-
bolic pathways to convert small precursor molecules into cellular termediate or coenzyme—an amino acid or ATP, for ex-
Metabolic Pathways
 Pathways Are Sequences of
Reactions
•  A metabolic pathway is a series of
reactions where the product of one
reaction becomes the substrate for the
next reaction.
•  Some metabolic pathways may consist of
only two steps while others may be a
dozen steps in length.
 Pathways Are Sequences of
Reactions

•  Individual metabolic pathways can take different forms.

•  A linear metabolic pathway is a series of independent enzyme-
catalyzed reactions in which the product of one reaction is the
substrate for the next reaction in the pathway.
•  A cyclic metabolic pathway is also a sequence of enzyme-catalyzed
steps, but the sequence forms a closed loop, so the intermediates
are regenerated with every turn of the cycle.
•  In a spiral metabolic pathway the same set of enzymes is used
repeatedly for lengthening or shortening a given molecule.
Single-step versus multistep
pathways
 Metabolic Pathways Are
Regulated

Feedback inhibition occurs when a product (usually the end product) of a

pathway controls the rate of its own synthesis through inhibition of an early step,
usually the first committed step.
Feed-forward activation occurs when a metabolite produced early in a pathway
activates an enzyme that catalyzes a reaction further down the pathway.
•  Each of the reactions is catalyzed
by an enzyme and they are all
reversible. Most reactions in living
cells have reached equilibrium so
the concentrations of B, C, D, and
E do not change very much.
•  The rate of flow is equivalent to
the flux in a pathway, and the
constant amount of water in each
beaker is analogous to the steady
state concentrations of
metabolites in a pathway.
 Anabolic pathways

Large molecules are synthesized from smaller ones by adding carbon (usually in
the form of CO2) and nitrogen (usually as NH4+). The main 4 pathways include
the citric acid cycle, which supplies the intermediates in amino acid biosynthesis,
and gluconeogenesis, which results in the production of glucose. The energy for
biosynthetic pathways is supplied by light in photosynthetic organisms or by the
breakdown of inorganic molecules in other autotrophs.
 Catabolic pathways

Overview of catabolic pathways. Amino acids, nucleotides, monosaccharides, and

fatty acids are formed by enzymatic hydrolysis of their respective polymers. They are
then degraded in oxidative reactions and energy is conserved in ATP and reduced
coenzymes (mostly NADH).
Compartmentation and
Interorgan Metabolism
 Bioenergetics
•  Is the quantitative study of energy
transductions—changes of one form of
energy into another—that occur in living
cells, and of the nature and function of the
chemical processes underlying these
transductions.
 Thermodynamics
•  The first law is the principle of the conservation of
energy: for any physical or chemical change, the total
amount of energy in the universe remains constant;
energy may change form or it may be transported from
one region to another, but it cannot be created or
destroyed.
•  The second law of thermodynamics, which can be stated
in several forms, says that the universe always tends
toward increasing disorder: in all natural processes, the
entropy of the universe increases.
•  Gibbs free energy, G,
expresses the amount of
energy capable of doing work
during a reaction at constant
temperature and pressure.
•  Enthalpy, H, is the heat
content of the reacting
system.
•  Entropy, S, is a quantitative
expression for the
randomness or disorder in a
system.
 •  Under standard
conditions 298 K, and 1
Relationships among K"eq, #G"#, and atm, ΔG°.
TABLE 13–3
the Direction of Chemical Reactions
•  In the biochemical stan-
Starting with all
components at 1 M, dard state, [H+] is 10-7 M
When K"eq is . . . #G"# is . . . the reaction . . .
'1.0 negative proceeds forward
(pH 7) and [H2O] is 55.5
1.0 zero is at equilibrium M.
(1.0 positive proceeds in reverse
•  Physical constants based
positive value of #G"$ means that the products of the re-
on this biochemical
action contain more free energy than the reactants, and
this reaction will tend to go in the reverse direction if we
standard state are called
start with 1.0 M concentrations of all components (stan- standard transformed
dard conditions). Table 13–3 summarizes these points.
constants and are
WORKED EXAMPLE 13–1 Calculation of !G"# written with a prime (such
Calculate the standard free-energy change of the reac-
tion catalyzed by the enzyme phosphoglucomutase as ΔG°’and K’eq)
Glucose 1-phosphate ∆ glucose 6-phosphate
•  standard free-energy
given that, starting with 20 mM glucose 1-phosphate and
no glucose 6-phosphate, the final equilibrium mixture at changes.
stant and each has its characteristic standard free-
Standard Free-Energy
energy change, !G"# 1 and !G"# 2 . As the two reactions
are sequential, B cancels out to give the overall reaction
Changes Are Additive
A ∆ C, which has its own equilibrium constant and thus
its own standard free-energy change, !G"# total. The !G"#
values of sequential chemical reactions are additive.
For the overall reaction A ∆ C, !G"# total is the sum of the
individual standard free-energy changes, !G"# 1 and !G"#
2,
of the two reactions: !G"#total $ !G"#
1 % !G"# 2.

(1) A 88n B !G1"#

(2) B 88n C !G2"#
Sum: A 88n C !G1"# % !G2"#

ThisThis
principle of bioenergetics explains how a thermody-
principle of bioenergetics explains how a thermodynamically
namically
unfavorableunfavorable (endergonic)
(endergonic) reaction reaction
can be driven in the forward can be
driven in
direction the forward
by coupling
common intermediate.
it to adirection by
highly exergonic coupling
reaction it
through to
a a highly
 namically
(2) unfavorable
B 88n C (endergonic)
!G2"# reaction can be
driven Sum: Standard Free-Energy
in the forward
A8 8ndirection
C
by coupling it to a highly
!G1"# % !G2"#
exergonic reaction through a common intermediate. For
Changes Are Additive
principle of bioenergetics explains how a thermody-
example, the synthesis of glucose 6-phosphate is the first
cally unfavorable (endergonic) reaction can be
step inforward
the utilization of glucose by many organisms:
n in•  For example, the synthesis of glucose 6-
the direction by coupling it to a highly
gonic reaction
Glucosethrough
P 88n a common
glucose intermediate.
6-phosphate H O For
phosphate
mple, the synthesisisof
% i the first step
glucose in the utilization
6-phosphate
% 2
is the first
!G"# $ 13.8 kJ/mol
in theof glucose by
utilization many organisms:
of glucose by many organisms:
The positive
Glucose % Pivalue of !G"# predicts
88n glucose that under
6-phosphate % H2Ostandard
conditions the reaction will tend not!G"#
to proceed
$ 13.8sponta-
kJ/mol
neously
positive in the
value ofdirection
!G"# predicts written. thatAnotherunder cellular reac-
standard
tion,
itions The
thethe hydrolysis
positive value of ΔG’°
reaction will oftend
ATP
predicts to ADP
that under
not standardand Pi, sponta-
conditions
to proceed is very
the reaction will tend not to proceed spontaneously in the direction
sly exergonic:
in written.
the direction written. Another cellular reac-
the hydrolysis of ATP to ADP and Pi, is very
gonic: ATP % H2O 88n ADP % Pi !G"# $ &30.5 kJ/mol

ATPThese
% H2two
O8
8nreactions
ADP % share
Pi the!G"#
common intermediates
$ &30.5 kJ/mol Pi
andreactions
e two H2O and may be expressed
share the commonas sequential reactions:P
intermediates
neously in the direction written. Another cellular reac-
tion, the hydrolysis of ATP to ADP and Pi, is very
exergonic:
ATP % H2O 88n ADP % Pi !G"# $ &30.5 kJ/mol

These two reactions share the common intermediates Pi

and H2O and may be expressed as sequential reactions:
(1) Glucose % Pi 88n glucose 6-phosphate % H2O
(2) ATP % H2O 88n ADP % Pi
Sum: ATP % glucose 88n ADP % glucose 6-phosphate

The overall standard free-energy change is obtained by

adding the !G"# values for individual reactions:
!G"# $ 13.8 kJ/mol % (&30.5 kJ/mol) $ &16.7 kJ/mol

The overall reaction is exergonic. In this case, energy

stored in ATP is used to drive the synthesis of glucose
•  Metabolically irreversible reactions are
catalyzed by enzymes whose activity is
regulated in order to prevent the reaction
from reaching equilibrium.
The energy produced by one biological reaction or process, such as the synthesis of
X ¬ Y in Reaction 10.15, is often coupled to a second reaction, such as the hydrolysis
of ATP. The first reaction would not otherwise occur spontaneously.

X + Y ∆ X¬Y
ATP + H2O ∆ ADP + Pi + H ! (10.15)

SAMPLE CALCULATION 10.2 Gibbs Free Energy Change

Q: In a rat hepatocyte, the concentrations of ATP, ADP, and the Gibbs free energy change for hydrolysis of ATP in this cell.
Pi are 3.4 mM, 1.3 mM, and 4.8 mM, respectively. Calculate How does this compare to the standard free energy change?

A: The actual Gibbs free energy change is calculated according to Equation 10.10.
3ADP43Pi4 3ADP43Pi4
¢Greaction = ¢G°¿reaction + RT ln = ¢G°reaction + 2.303 RT log
3ATP4 3ATP4

When known values and constants are substituted (with concentrations expressed as molar values), assuming pH7.0 and 25°C.
-1 -1 -1 (1.3 * 10-3)(4.8 * 10-3)
¢G = -32000 J mol + (8.31 JK mol )(298 K) c2.303 log d
(3.4 * 10-3)
¢G = -32000 J mol-1 + (2480 J mol-1) 32.303 log (1.8 * 10-3)4

¢G = -32000 J mol-1 - 16 000 J mol-1

¢G = -48 000 J mol-1 = -48 kJ mol-1

The actual free energy change is about 11/2 times the standard free energy change.
n
rt NADH ATP
•  The production of ATP is one of the most important
n of NADH
reactionsand ATP. As mentioned above, the citric acid
in metabolism.
oth • anabolic and catabolic
The synthesis of most ATP metabolism.
is coupled to membrane-
oduction associated
of ATPelectron
is onetransport.
of the most important reaction
is of•  most
In electron
ATPtransport, the energy
is coupled of reduced coenzymes
to membrane-associated el
such as NADH is used to generate an electrochemical
). In electron
gradient transport, the energy
of protons across of reduced coenzymes
a cell membrane.
rate • anThe
electrochemical
potential energygradient of protons
of this gradient is used across
to driveathe
cell me
y of this gradient is harnessed
phosphorylation of ADP to ATP. to drive the phosphorylatio

ADP + Pi ¡ ATP + H2O

hat the reactions of membrane-associated electron transp

ATP
 ATP
•  Several factors contribute to the large
amount of energy released during
hydrolysis of the phosphoanhydride
linkages of ATP.
•  Electrostatic repulsion. Electrostatic
repulsion among the negatively charged
oxygen atoms of the phosphoanhydride
groups of ATP is less after hydrolysis.
•  Solvation effects. The products of
hydrolysis, ADP and inorganic
phosphate, or AMP and inorganic
pyrophosphate, are better solvated than
ATP itself.
•  Resonance stabilization. The
products of hydrolysis are more stable
than ATP.
Synthesis of acetyl CoA from acetate,
catalyzed by acetyl-CoA synthetase.
Reactions involving thioesters, such as acetyl CoA, release
amounts of energy comparable to that of ATP hydrolysis.
This substrate-level phosphorylation conserves energy used in the
formation of succinyl CoA as ATP equivalents. The energy of
thioesters also drives the synthesis of fatty acids.
NAD+ is reduced to NADH in coupled reactions where electrons are transferred
from a metabolite to NAD+. The reduced form of the coenzyme (NADH)
becomes a source of electrons in other oxidation–reduction reactions.