Metabolic maps Figure 17.2 portray the principal reactions of the intermediary metabolism of carbohydrates, lipids, amino acids, nucleotides, and their deriva-tives.. Protein-centric map
Trang 1mosphere for reuse by the photoautotrophs In effect, solar energy is converted to
the chemical energy of organic molecules by photoautotrophs, and heterotrophs
recover this energy by metabolizing the organic substances The flow of energy in the
biosphere is thus conveyed within the carbon cycle, and the impetus driving the
cycle is light energy
Metabolic maps (Figure 17.2) portray the principal reactions of the intermediary
metabolism of carbohydrates, lipids, amino acids, nucleotides, and their
deriva-tives These maps are very complex at first glance and seem to be virtually
impos-sible to learn easily Despite their appearance, these maps become easy to follow
once the major metabolic routes are known and their functions are understood
The underlying order of metabolism and the important interrelationships between
the various pathways then appear as simple patterns against the seemingly
compli-cated background
The Metabolic Map Can Be Viewed as a Set of Dots and Lines
One interesting transformation of the intermediary metabolism map is to represent
each intermediate as a black dot and each enzyme as a line (Figure 17.3) Then, the
more than 1000 different enzymes and substrates are represented by just two symbols
This chart has about 520 dots (intermediates) Table 17.2 lists the numbers of dots that
have one or two or more lines (enzymes) associated with them Thus, this table
classi-fies intermediates by the number of enzymes that act upon them A dot connected to
just a single line must be either a nutrient, a storage form, an end product, or an
ex-cretory product of metabolism Also, because many pathways tend to proceed in only
one direction (that is, they are essentially irreversible under physiological conditions),
a dot connected to just two lines is probably an intermediate in only one pathway and
has only one fate in metabolism If three lines are connected to a dot, that
intermedi-ate has at least two possible metabolic fintermedi-ates; four lines, three fintermedi-ates; and so on Note that
about 80% of the intermediates connect to only one or two lines and thus have only a
single role in the cell However, intermediates at branch points are subject to a variety
of fates In such instances, the pathway followed is an important regulatory choice
In-deed, whether any substrate is routed down a particular metabolic pathway is the
con-sequence of a regulatory decision made in response to the cell’s (or organism’s)
mo-mentary requirements for energy or nutrition The regulation of metabolism is an
interesting and important subject to which we will return often
Alternative Models Can Provide New Insights into Pathways
Alternative mappings of metabolic reactions have been postulated for several
rea-sons First and most obviously, the sheer complexity of pathways has prompted
biochemists to seek simpler portrayals of an organism’s chemistry Second,
tradi-tional metabolite-focused maps (Figure 17.4a) do not provide insight into the
spa-tial and temporal organization of the metabolites and the enzymes that
intercon-vert them Even more significantly, the rise of genomics (the study of the whole
genomes of organisms), transcriptomics (the study of global messenger RNA
ex-pression), and proteomics (the study of the totality of proteins) has provoked
fresh conceptions of biological order and function For example, Juliet Gerrard
has proposed that metabolic maps be recast in protein-centric presentations (Figure
17.4b) In such maps, the metabolites and the enzymes that interconvert them are
transposed, revealing a new emphasis—the metabolites are “signals” in a cellular
network of proteins
Protein-centric maps may be condensed and simplified by realizing that some
pathway enzymes are clustered in multienzyme complexes and that metabolites are
Lines Dots
TABLE 17.2 Number of Dots (Intermediates)
in the Metabolic Map of Figure 17.2, and the Number of Lines Associated with Them
Trang 2ANIMATED FIGURE 17.2 A metabolic map, indicating the reactions of intermediary metabo-lism and the enzymes that catalyze them More than 500 different chemical intermediates, or metabolites, and
a greater number of enzymes are represented here (Source: From Donald Nicholson, Map #22, © International Union of
See this figure animated at www.cengage.com/login.
Trang 3FIGURE 17.3 The metabolic map as a set of dots and lines The heavy dots and lines trace the central
energy-releasing pathways known as glycolysis and the citric acid cycle.(Adapted from Alberts, B., et al., 1989 Molecular
Trang 4Biol-516 Chapter 17 Metabolism: An Overview
literally passed from enzyme to enzyme within such clusters (Figure 17.4c) The re-sult is a simplified representation of metabolic networks, containing only the es-sential signaling information Metabolic maps are representations of large amounts
of information Conceptualizing them in different formats enables biochemists to analyze vast amounts of information in new and insightful ways
Multienzyme Systems May Take Different Forms
The individual metabolic pathways of anabolism and catabolism consist of se-quential enzymatic steps (Figure 17.5) Several types of organization are possible The enzymes of some multienzyme systems may exist as physically separate, soluble entities, with diffusing intermediates (Figure 17.5a) In other instances, the en-zymes of a pathway are collected to form a discrete multienzyme complex, and the substrate is sequentially modified as it is passed along from enzyme to enzyme (Fig-ure 17.5b) This type of organization has the advantage that intermediates are not lost or diluted by diffusion In a third pattern of organization, the enzymes common
to a pathway reside together as a membrane-bound system (Figure 17.5c) In this case,
the enzyme participants (and perhaps the substrates as well) must diffuse in just the two dimensions of the membrane to interact with their neighbors
As research reveals the ultrastructural organization of the cell in ever greater de-tail, more and more of the so-called soluble enzyme systems are found to be physi-cally united into functional complexes Thus, in many (perhaps all) metabolic
path-A
(a)
E1 E2 E3
E6
E4 E5
G
E7 H
E8 I
E9 J
E10 E14
K
E11 L
E15 P
E12 M
E13 N
E16
O
P
L
(b)
A E
1
E6
B
C
E7 G
E8 H
E9 I
J
E10 D
E11 K
E14 D
E16
E15
E12 L
E13 M
N
E2 C E3 D E4 E E5 F
D
C
N
P
P
E3
(c)
A
E16
D D
Enzymes
1 and 2
Enzymes
4 and 5
Enzymes
6 to 9
Enzymes
10 and 11
Enzymes
14 and 15
Enzymes
12 and 13
FIGURE 17.4 (a) The traditional view of a metabolic pathway is
metabolite-centric (b) Gerrard has proposed that a protein-centric view is more informative for some purposes (c) A simplified version
of the protein-centric view where proteins in the pathway form multifunctional complexes.
Trang 5ways, the consecutively acting enzymes are associated into stable multienzyme
com-plexes that are sometimes referred to as metabolons, a word meaning “units of
metabolism.”
the Core of Metabolic Pathways?
Metabolism serves two fundamentally different purposes: the generation of energy
to drive vital functions and the synthesis of biological molecules To achieve these
ends, metabolism consists largely of two contrasting processes: catabolism and
an-abolism Catabolic pathways are characteristically energy yielding, whereas anabolic
path-ways are energy requiring Catabolism involves the oxidative degradation of complex
nutrient molecules (carbohydrates, lipids, and proteins) obtained either from the
environment or from cellular reserves The breakdown of these molecules by
ca-tabolism leads to the formation of simpler molecules such as lactic acid, ethanol,
carbon dioxide, urea, or ammonia Catabolic reactions are usually exergonic, and
often the chemical energy released is captured in the form of ATP (see Chapter 3)
Because catabolism is oxidative for the most part, part of the chemical energy may
be conserved as energy-rich electrons transferred to the coenzymes NAD and
NADP These two reduced coenzymes have very different metabolic roles: NAD
reduction is part of catabolism; NADPH oxidation is an important aspect of
anabolism The energy released upon oxidation of NADH is coupled to the
phos-phorylation of ADP in aerobic cells, and so NADH oxidation back to NADserves
to generate more ATP; in contrast, NADPH is the source of the reducing power
needed to drive reductive biosynthetic reactions
Thermodynamic considerations demand that the energy necessary for
biosyn-thesis of any substance exceed the energy available from its catabolism Otherwise,
(a)
(b)
(c)
FIGURE 17.5 Schematic representation of types of multi-enzyme systems carrying out a metabolic pathway:
(a) Physically separate, soluble enzymes with diffusing
intermediates (b) A multienzyme complex Substrate
enters the complex and becomes bound and then se-quentially modified by enzymes E 1 to E 5 before product
is released No intermediates are free to diffuse away.
(c) A membrane-bound multienzyme system.
Trang 6518 Chapter 17 Metabolism: An Overview
organisms could achieve the status of perpetual motion machines: A few molecules
of substrate whose catabolism yielded more ATP than required for its resynthesis would allow the cell to cycle this substance and harvest an endless supply of energy
Anabolism Is Biosynthesis Anabolismis a synthetic process in which the varied and complex biomolecules (pro-teins, nucleic acids, polysaccharides, and lipids) are assembled from simpler precur-sors Such biosynthesis involves the formation of new covalent bonds, and an input
of chemical energy is necessary to drive such endergonic processes The ATP gener-ated by catabolism provides this energy Furthermore, NADPH is an excellent donor
of high-energy electrons for the reductive reactions of anabolism Despite their di-vergent roles, anabolism and catabolism are interrelated in that the products of one provide the substrates of the other (Figure 17.6) Many metabolic intermediates are shared between the two processes, and the precursors needed by anabolic pathways are found among the products of catabolism
Anabolism and Catabolism Are Not Mutually Exclusive
Interestingly, anabolism and catabolism occur simultaneously in the cell The con-flicting demands of concomitant catabolism and anabolism are managed by cells
in two ways First, the cell maintains tight and separate regulation of both catabo-lism and anabocatabo-lism, so metabolic needs are served in an immediate and orderly fashion Second, competing metabolic pathways are often localized within differ-ent cellular compartmdiffer-ents Isolating opposing activities within distinct compart-ments, such as separate organelles, avoids interference between them For
exam-ple, the enzymes responsible for catabolism of fatty acids, the fatty acid oxidation
pathway, are localized within mitochondria In contrast, fatty acid biosynthesis takes
place in the cytosol In subsequent chapters, we shall see that the particular mole-cular interactions responsible for the regulation of metabolism become important for an understanding and appreciation of metabolic biochemistry
The Pathways of Catabolism Converge to a Few End Products
If we survey the catabolism of the principal energy-yielding nutrients (carbohy-drates, lipids, and proteins) in a typical heterotrophic cell, we see that the degra-dation of these substances involves a succession of enzymatic reactions In the
pres-ence of oxygen (aerobic catabolism), these molecules are degraded ultimately to
carbon dioxide, water, and ammonia Aerobic catabolism consists of three distinct
Energy-yielding nutrients
Chemical energy
H2O
CO2
NH3
Carbohydrates Fats
Proteins
Cell macromolecules
Proteins Polysaccharides Lipids Nucleic acids
Amino acids Sugars Fatty acids Nitrogenous bases
Catabolism (oxidative, exergonic)
Anabolism (reductive, endergonic)
ATP ATP
ATP ATP ATP
NADPH
NADPH
NADPH NADPH
NADPH
FIGURE 17.6 Energy relationships between the
path-ways of catabolism and anabolism Oxidative, exergonic
pathways of catabolism release free energy and
reduc-ing power that are captured in the form of ATP and
NADPH, respectively Anabolic processes are endergonic,
consuming chemical energy in the form of ATP and
using NADPH as a source of high-energy electrons for
reductive purposes.
Trang 7stages In stage 1, the nutrient macromolecules are broken down into their
respec-tive building blocks Despite the great diversity of macromolecules, these building
blocks represent a rather limited number of products Proteins yield up their
20 component amino acids, polysaccharides give rise to carbohydrate units that are
convertible to glucose, and lipids are broken down into glycerol and fatty acids
(Figure 17.7)
In stage 2, the collection of product building blocks generated in stage 1 is further
degraded to yield an even more limited set of simpler metabolic intermediates The
S t a g e 2:
S t a g e 3:
NH3
Proteins Polysaccharides Lipids The various kinds of proteins, polysaccharides, and
fats are broken down into their component
building blocks, which are relatively few in number.
Amino acids Glycerol, fatty acids
Pentoses, hexoses
Glucose
Glyceraldehyde-3-phosphate
Pyruvate
Acetyl-CoA
Building block molecules
The various building blocks are degraded into a
common product, the acetyl groups of acetyl-CoA. Glycolysis
Oxidative phosphorylation
H 2 O
Common degradation product
Catabolism converges via the citric acid cycle to
three principal end products: water, carbon dioxide,
and ammonia
Simple, small end products of catabolism
End
products
Citric acid cycle
CO 2
FIGURE 17.7 The three stages of catabolism.
Stage 1: Proteins, polysaccharides, and lipids are broken
down into their component building blocks, which are
relatively few in number Stage 2: The various building
blocks are degraded into the common product, the
acetyl groups of acetyl-CoA Stage 3: Catabolism
con-verges to three principal end products: water, carbon dioxide, and ammonia.
Trang 8520 Chapter 17 Metabolism: An Overview
deamination of amino acids leaves -keto acid carbon skeletons Several of these
-keto acids are citric acid cycle intermediates and are fed directly into stage 3
catab-olism via this cycle Others are converted either to the three-carbon -keto acid pyru-vate or to the acetyl groups of acetyl -coenzyme A (acetyl-CoA) Glucose and the glycerol
from lipids also generate pyruvate, whereas the fatty acids are broken into two-carbon
units that appear as acetyl-CoA Because pyruvate also gives rise to acetyl-CoA, we see
that the degradation of macromolecular nutrients converges to a common end prod-uct, acetyl-CoA (Figure 17.7)
The combustion of the acetyl groups of acetyl-CoA by the citric acid cycle and
ox-idative phosphorylation to produce CO2and H2O represents stage 3 of catabolism The
end products of the citric acid cycle, CO2and H2O, are the ultimate waste products
of aerobic catabolism As we shall see in Chapter 19, the oxidation of acetyl-CoA dur-ing stage 3 metabolism generates most of the energy produced by the cell
Anabolic Pathways Diverge, Synthesizing an Astounding Variety
of Biomolecules from a Limited Set of Building Blocks
A rather limited collection of simple precursor molecules is sufficient to provide for the biosynthesis of virtually any cellular constituent, be it protein, nucleic acid, lipid, or polysaccharide All of these substances are constructed from appropriate building blocks via the pathways of anabolism In turn, the building blocks (amino acids, nucleotides, sugars, and fatty acids) can be generated from metabolites in the cell For example, amino acids can be formed by amination of the corresponding
-keto acid carbon skeletons, and pyruvate can be converted to hexoses for
poly-saccharide biosynthesis
Amphibolic Intermediates Play Dual Roles
Certain of the central pathways of intermediary metabolism, such as the citric acid cycle, and many metabolites of other pathways have dual purposes—they serve in both catabolism and anabolism This dual nature is reflected in the designation of such
pathways as amphibolic rather than solely catabolic or anabolic In any event, in
con-trast to catabolism—which converges to the common intermediate, acetyl-CoA—the pathways of anabolism diverge from a small group of simple metabolic intermediates
to yield a spectacular variety of cellular constituents
Corresponding Pathways of Catabolism and Anabolism Differ
in Important Ways
The anabolic pathway for synthesis of a given end product usually does not precisely match the pathway used for catabolism of the same substance Some of the interme-diates may be common to steps in both pathways, but different enzymatic reactions and unique metabolites characterize other steps A good example of these differences
is found in a comparison of the catabolism of glucose to pyruvic acid by the pathway
of glycolysis and the biosynthesis of glucose from pyruvate by the pathway called
glu-coneogenesis The glycolytic pathway from glucose to pyruvate consists of 10 enzymes.
Although it may seem efficient for glucose synthesis from pyruvate to proceed by a versal of all 10 steps, gluconeogenesis uses only seven of the glycolytic enzymes in re-verse, replacing those remaining with four enzymes specific to glucose biosynthesis
In similar fashion, the pathway responsible for degrading proteins to amino acids dif-fers from the protein synthesis system, and the oxidative degradation of fatty acids to two-carbon acetyl-CoA groups does not follow the same reaction path as the biosyn-thesis of fatty acids from acetyl-CoA
Metabolic Regulation Requires Different Pathways for Oppositely Directed Metabolic Sequences A second reason for different pathways serving in opposite metabolic directions is that such pathways must be independently regulated If ca-tabolism and anabolism passed along the same set of metabolic tracks, equilibrium considerations would dictate that slowing the traffic in one direction by inhibiting
Amphi is from the Greek for “on both sides.”
Trang 9a particular enzymatic reaction would necessarily slow traffic in the opposite
direc-tion Independent regulation of anabolism and catabolism can be accomplished
only if these two contrasting processes move along different routes or, in the case of
shared pathways, the rate-limiting steps serving as the points of regulation are
cat-alyzed by enzymes that are unique to each opposing sequence (Figure 17.8)
ATP Serves in a Cellular Energy Cycle
We saw in Chapter 3 that ATP is the energy currency of cells In phototrophs, ATP
is one of the two energy-rich primary products resulting from the transformation of
light energy into chemical energy (The other is NADPH; see the following
discus-sion.) In heterotrophs, the pathways of catabolism have as their major purpose the
release of free energy that can be captured in the form of energy-rich phosphoric
anhydride bonds in ATP In turn, ATP provides the energy that drives the manifold
activities of all living cells—the synthesis of complex biomolecules, the osmotic
work involved in transporting substances into cells, the work of cell motility, and the
work of muscle contraction These diverse activities are all powered by energy
re-leased in the hydrolysis of ATP to ADP and Pi Thus, there is an energy cycle in cells
where ATP serves as the vessel carrying energy from photosynthesis or catabolism to
the energy-requiring processes unique to living cells (Figure 17.9)
A
E 1
B
C
D
E
P
E 3
E 4
E 5
A
P
M
L
K
J
E 6
E 7
E 8
E 9
E 10
A
P
A
P
E 1
E 2
E 4
E 5
M L K J
E 9
E 8
E 7
B C D E
E 6
E 2
E 3
E 4
E 5
E 2
E 4
E 5
+
+
E 10
E 2
(a) Regulated
step
Regulated step Activation of one mode is accompanied by
reciprocal inhibition of the other mode.
Catabolic
mode
Anabolic mode
(b)
Catabolic mode
Anabolic mode
FIGURE 17.8 Parallel pathways of catabolism and an-abolism must differ in at least one metabolic step in order that they can be regulated independently Shown here are two possible arrangements of opposing
cata-bolic and anacata-bolic sequences between A and P (a) The
parallel sequences proceed via independent routes.
(b) Only one reaction has two different enzymes, a
cata-bolic one (E 3 ) and its anabolic counterpart (E 6 ) These provide sites for regulation.
ATP
O 2
H 2 O
a.
b.
c.
Fuels Photosynthesis
Light
energy
The ATP Cycle
P i
+
CO 2
ADP
Biosynthesis Osmotic work Cell motility/muscle contraction
ATP hydrolysis
Catabolism
FIGURE 17.9 The ATP cycle in cells ATP is formed via photosynthesis in phototrophic cells or catabolism in heterotrophic cells Energy-requiring cellular activities are powered by ATP hydrolysis, liberating ADP and P
Trang 10522 Chapter 17 Metabolism: An Overview
NADⴙCollects Electrons Released in Catabolism
The substrates of catabolism—proteins, carbohydrates, and lipids—are good sources
of chemical energy because the carbon atoms in these molecules are in a relatively reduced state (Figure 17.10) In the oxidative reactions of catabolism, reducing
equivalents are released from these substrates, often in the form of hydride ions (a
proton coupled with two electrons, H⬊) These hydride ions are transferred in
en-zymatic dehydrogenase reactions from the substrates to NADmolecules, reducing them to NADH A second proton accompanies these reactions, appearing in the overall equation as H (Figure 17.11) In turn, NADH is oxidized back to NAD when it transfers its reducing equivalents to electron acceptor systems that are part
of the metabolic apparatus of the mitochondria The ultimate oxidizing agent (e ac-ceptor) is O2, becoming reduced to H2O
Oxidation reactions are exergonic, and the energy released is coupled with the
formation of ATP in a process called oxidative phosphorylation The NAD–NADH
system can be viewed as a shuttle that carries the electrons released from catabolic
substrates to the mitochondria, where they are transferred to O2, the ultimate elec-tron acceptor in catabolism In the process, the free energy released is trapped in ATP The NADH cycle is an important player in the transformation of the chemical energy of carbon compounds into the chemical energy of phosphoric anhydride bonds Such transformations of energy from one form to another are referred to as
energy transduction.Oxidative phosphorylation is one cellular mechanism for en-ergy transduction Chapter 20 is devoted to electron transport reactions and oxida-tive phosphorylation
CH2
H
> C
OH
>
O
C > C
O
OH
>
O C O More
reduced state
Less reduced state
FIGURE 17.10 Comparison of the state of reduction
of carbon atoms in biomolecules: OCH 2 O (fats)
OCHOHO (carbohydrates) HECPO (carbonyls)
OCOOH (carboxyls) CO 2 (carbon dioxide, the final
product of catabolism).
P
+
H
CH2 –O
O O O P
O
O
N+
C NH2 O
CH2 O
OH OH
OH OH
H
NH2 N
N
N
N
CH3CH2OH
Reduction
N
C NH2
O H H
P
CH2 –O
O O O P
O
O
CH2 O
OH OH
OH OH
NH2 N
N
N
N
+ CH3CH
O
+
Acetaldehyde
–
H +
FIGURE 17.11 Hydrogen and electrons released in the course of oxidative catabolism are transferred as hydride ions to the pyridine nucleotide, NAD , to form NADH H in dehydrogenase reactions of the type
AH 2 NAD ⎯⎯→ A NADH H
The reaction shown is catalyzed by alcohol dehydrogenase.