You are on page 1of 11

Overview of Metabolic Pathways: Catabolism

Biological cells have a daunting task. They must carry out 1000s of different chemical reactions
required to carry out cell function. These reactions can include opposing goals such as energy
production and energy storage, macromolecule degradation and synthesis, and breakdown and
synthesis of small molecules. All of these reactions are catalyzed by proteins and RNAs
enzymes whose activities must be regulated, again through chemical reactions, to avoid a futile
and energy wasting scenario of having opposing pathways functioning simultaneously in a cell.
Metabolism can be divided into two main parts, catabolism, the degradation of molecules,
usually to produce energy or small molecules useful for cell function, and anabolism, the
synthesis of larger biomolecules from small precursors.

CATABOLISM
Catabolic reactions involve the breakdown of carbohydrates, lipids, proteins, and nucleic acids to
produce smaller molecules and biological energy in the form of heat or small thermodynamically
reactive molecules like ATP whose further degradation can drive endergonic process such as
biosynthesis. Our whole world is reliant on the oxidation of organic hydrocarbons to water and
carbon dioxide to produce energy (at the expense of releasing a potent greenhouse gas, CO 2). In
the biological world, reduced molecules like fatty acids and partially oxidized molecules such as
glucose polymers (glycogen, starch), as well as simple sugars, can be partially or fully oxidized
to ultimately produce CO2as well. Energy released from oxidative reactions is used to produce
molecules like ATP as well as heat. Oxidative pathways include glycolysis, the tricarboxylic
acid cycle (aka Kreb's cycle) and mitochondrial oxidative phosphorylation/electron transport. To
fully oxidize carbon in glucose and fatty acids to carbon dioxide requires splitting C-C bonds and
the availability of series of oxidizing agents that can perform controlled, step-wise oxidation
reactions, analogous to the sequential oxidation of methane, CH 4 to methanol (CH3OH),
formaldehyde (CH2O) and carbon dixoxide.

Glycolysis: This most primitive of metabolic pathways is found in perhaps all


organisms. In glycolysis, glucose (C6H12O6), a 6C molecule, is split (or lysed) into two, 3C
carbon molecules, glyceraldehyde-3-phosphate, which are then partially oxidized
underanaerobic conditions (without O2) to form two molecules of pyruvate (CH 3COCO2-).
Instead of the very strong oxidizing agent, O2, a weaker one, NAD+ is used, which is reduced in
the process to form NADH. Since none of the carbon atoms is oxidized to the state of CO 2, little
energy is released compared to the complete oxidation to CO 2. This pathway comes to a
screeching halt if all cellular NAD+is converted to NADH as NAD+ is not replenished by the
simple act of breathing as is the case with O2 in aerobic oxidation. To prevent the depletion of
NAD+ from inhibiting the cycle and to allow the cycle to continue under anaerobic conditions,
excess NADH is reconverted to NAD+ when the other product of glycolysis, pyruvate is
converted to lactate by the enzyme lactate dehydrogenase. Glycolysis occurs in the cytoplasm of
the cell.

Figure: Summary of Glycolysis

Tricarboxylic Acid (Kreb's) Cycle: The TCA cycle is an aerobic pathway which takes
place in an intracellular organelle called the mitochondria. It takes pyruvate, the incompletely
oxidized product from glycolysis, and finishes the job of oxidizing the 3C atoms all the way to
CO2. First the pyruvate moves into the mitochondria where is is oxidized to the 2C molecule
acetylCoA with the release of one CO2 by the enzyme pyruvate dehydrogenase. The acetyl-CoA
then enters the TCA cycle where two more CO 2 are released. As in glycolysis, C-C bonds are
cleaved and C is oxidized by NAD+ and another related oxidizing agent, FAD. What is very
different about this pathway is that instead of being a series of linear, sequential reactions with
one reactant (glucose) and one product (two pryuvates), it is a cyclic pathway. This has
significant consequences since if any of the reactants within the pathways becomes depleted, the
whole cyclic pathway can slow down and stop. To see how this happens consider the molecule
oxaloacetate (OAA) which condenses with acetyl-CoA to form citrate (see diagram below). In
this reaction, one OAA is consumed. However, when the cycle returns, one malate is converted
to OAA so there is no net loss of OAA, unless OAA is pulled out of the TCA cycle for other
reactions, which happens.
Figure: Pyruvate Dehydrogenase (mitochondrial) and the TCA Cycle

Mitochondrial Oxidative Phosphorylation/Electron Transport: The TCA cycle


accomplishes what glycolysis didn't, that is the cleavage of all C-C bonds in glucose (in the form
of pyruvate and acetyl-CoA, and the complete oxidation of all C atoms to CO 2. Yet two problem
remains. The pool of oxidizing molecules, NAD+ and FAD get converted to their reduced
forms, NADH and FADH2. Unless NAD+ and FAD are regenerated, as was the case in anaerobic
conditions when pyruvate gets converted to lacate, the pathway would again come to a grinding
halt. In addition, not much ATP is made in the cycle (in the form of a related molecule GTP).
Both these problems are resolved as the resulting NADH and FADH 2 formed are reoxidized by
mitochondrial membrane enzyme complexes which pass electrons from the oxidized NADH and
FADH2 to increasingly potent oxidizing agents until they are accepted by the powerful oxidant
O2,which is converted reduced to water. The net oxidation of NADH and FADH2 by dioxygen is
greatly exergonic, and the energy released by the process drives the synthesis of ATP from ADP
and Pi by an mitochondrial enzyme complex, the F0F1ATPase.
Figure: Mitochondrial Electron Transport/Oxidative Phosphorylation

Feeder Pathways: Other catabolic pathways produce products that can enter glycolysis or the
TCA cycle. Two examples are given below.
Complex carbohydrates: In mammals, the major carbohydrate storage molecule is
glycogen, a polymer of glucose linked a1-4 with a1-6 branches. The terminal acetal linkages in
this highly branched polymer is cleaved sequentially at the ends not through hydrolysis but
through phosphorolysis to produce lots of glucose-1-phosphate which can enter glycolysis.

Lipids: Lipids are stored mostly as triacylglycerides in fat cells (adipocytes). When
needed for energy, fatty acids are hydrolyzed from the glycerol backbone of the triacylglyceride,
and send into cells where they broken down in an oxidative process to form acetyl-CoA with the
concomitant production of lots of NADH and FADH 2. These can then enter the mitochondrial
oxidative phosphorylation/electrons transport system, which produces, under aerobic conditions,
lots of ATP.

Proteins: When intracellular proteins get degraded, they from individual amino acids. The
amine N is lost as it enters the urea cycle. The rest of some amino acid structures can be
ultimately converted to acetyl-CoA or keto acids (like alpha-ketoglutarate- a-KG) that are TCA
intermediate. These amino acids are called ketogenic. Alternatively, some amino acids, after
deamination, are coveted to pyruvate which can either enter the TCA cycle or in the liver be used
to synthesize glucose in an anabolic process. These amino acids are called glucogenic. Chemical
reactions such as these can be used to replenish intermediates in the TCA cycle which can
become depleted as they are withdraw for other reactions.

Now on to anabolic reactions.

Overview of Metabolic Pathways: Anabolism

Anabolic reactions are those that lead to the synthesis of biomolecules. In contrast to the
catabolic reactions just discussed (glycolysis, TCA cycle and electron transport/oxidative
phosphorylation) which lead to the oxidative degradation of carbohydrates and fatty acids and
energy release, anabolic reactions lead to the synthesis of more complex biomolecules including
biopolymers (glycogen, proteins, nucleic acids) and complex lipids. Many biosynthetic
reactions, including those for fatty acid synthesis, are reductive and hence require reducing
agents. Reductive biosynthesis and complex polymer formation require energy input, usually in
the form of ATP whose exergonic cleavage is coupled to endergonic biosynthesis.
Cells have evolved interesting mechanism so as not to have oxidative degradation reactions
(which release energy) proceed at the same time and in the same cell as reductive biosynthesis
(which requires energy input). Consider this scenario. You dive into a liver cell and find
palmitic acid, a 16C fatty acid. From where did it come? Was it just synthesized by the liver cell
or did it just enter the cell from a distant location such as adipocytes (fat cells). Should it be

oxidized, which should happen if there is a demand for energy production by the cell, or should
the liver cell export it, perhaps to adipocytes, which might happen if there is an excess of energy
storage molecules? Cells have devised many ways to distinguish these opposing needs. One is
by using a slightly different pool of redox reagents for anabolic and catabolic reactions.
Oxidative degradation reactions typically use the redox pair NAD+/NADH (or FAD/FADH2)
while reductive biosynthesis often uses phosphorylated variants of NAD +, NADP+/NADPH. In
addition, cells often carry out competing reactions in different cellular compartments. Fatty acid
oxidation of our example molecule (palmitic acid) occurs in the mitochondrial matrix, while
reductive fatty acid synthesis occurs in the cytoplasm of the cell. Fatty acids entering the cell
destined for oxidative degradation are transported into the mitochondria by the carnitine
transport system. This transport system is inhibited under conditions when fatty acid synthesis is
favored. We will discuss the regulation of metabolic pathways in a subsequent section. One of
the main methods, as we will see, is to activate or inhibit key enzymes in the pathways under a
given set of cellular conditions. The key enzyme in fatty acid synthesis, acetyl-CoA carboxylase,
is inhibited when cellular conditions require fatty acid oxidation.
The following examples give short descriptions of anabolic pathways. Compare them to the
catabolic pathways from the previous section.

Glucose synthesis, better known as Gluconeogenesis: In glycolysis, glucose


(C6H12O6), a 6C molecule, is converted to two, 3C molecules (pyruvate) in an oxidative process
that requires NAD+ and makes two net ATP molecules. In a few organs, most predominately in
the liver, the reverse pathway can take place. The liver does this to provide glucose to the brain
when the body is deficient in circulating glucose, for example, under fasting and starving
conditions. (The liver under these conditions can get its energy from oxidation of fatty acids).
The reactions in gluconeogenesis are the same reactions in glycolysis but run in reverse, with the
exception of three glycolytic steps which are essentially irreversible. These three steps have
bypass enzymes in the gluconeogenesis pathway. Although the synthesis of glucose is a
reductive pathway, it uses NADH instead of NADPH as the redundant as the same enzyme used
in glycolysis is simply run in reverse. Gluconeogenesis, which also occurs in the cortex of the
kidney, is more than just a simple reversal of glycolysis, however. It can be thought of as the net
synthesis of glucose from non-carbohydrate precursors. Pyruvate, as seen in the section on
catabolism, can be formed from protein degradation to glucogenic amino acids which can be
converted to pyruvate. It can also be formed from triacylglycerides from the 3C molecule
glycerol formed and released from adipocytes after hydrolysis of three fatty acids from
triacylglycerides. However, in humans, glucose can not be made in net fashion from fatty acids.
Fatty acids can be converted to acetyl-CoA by fatty acid oxidation. The resulting acetyl-CoA
can not form pyruvate since the enzyme that catalyzes the formation for acetyl-CoA from
pyruvate, pyruvate dehydrogenase, is irreversible and there is no bypass reaction known. The
acetyl-CoA can enter the TCA cycle but since the pathway is cyclic and proceeds in one
direction, it can not form in net fashion oxaloacetate. Although oxaloacetate can be remove from
the TCA cycle and be use to form phosphoenolpyuvate, a glycolytic intermediate, one acetylCoA condenses with one oxaloacetate to form citrate which leads back to one oxaloacetate.
Hence fatty acids can not be converted to glucose and other sugars in a net fashion.
Figure: Gluconeogenesis

Pentose Phosphate Shunt: This two-part pathway doesn't appear to start as a reductive
biosynthetic pathway as the first part is the oxidative conversion of a glycolytic intermediate,
glucose-6-phosphate, to ribulose-5-phosphate. The next, nonoxidative branch leads to the
formation of ribose-5-phosphate, a key biosynthetic intermediate in nucleic acid synthesis as
well as erthyrose-4-phosphate used for biosynthesis of aromatic amino acids . The oxidative
branch is important in reductive biosynthesis as it is a major source of the reductant NADPH
used in biosynthetic reactions.

Fatty acid and isoprenoid/sterol biosynthesis: Acetyl-CoA is the source of carbon


atoms for the synthesis of more complex lipids such as fatty acids, isoprenoids, and sterols.
When energy needs in a cell are not high, citrate, the condensation product of oxaloacetate and
acetyl-CoA in the TCA cycle, builds up in the mitochondrial matrix. It is then transported by the
citrate transporter (an inner mitochondrial membrane protein) to the cytoplasm, where it is
cleaved back to oxaloacetate and acetyl-CoA by the cytoplasmic enzyme citrate lyase. The
oxaloacetate is returned to the mitochondria by conversion first to malate (reduction reaction

using NADH), which can move back into the mitochondria through the malate transporter, or
further conversion to pyruate, using the cytosolic malic enzyme, which uses NADP + to oxidize
malate to pyruvate which then enters the mitochondria. The acetyl-CoA formed in the
cytoplasm can then be used in reductive biosynthesis using NADPH as the reductant to form
fatty acids, isoprenoids, and sterols. The NADPH for the reduction comes from the oxidative
branch of the pentose phosphate pathway and from the reaction catalyzed by malic enzyme. The
liver cells can still run the glycolytic pathway as the NADH/NAD + ratio is low in the cytoplasm
while NADPH/NADP+ ratio is high.

Now its time to see how the various pathways fit together to form an integrated set of pathways.
There is a very large number of metabolic pathways. In humans, the most important
metabolic pathways are:
glycolysis - glucose oxidation in order to obtain ATP
citric acid cycle (Krebs' cycle) - acetyl-CoA oxidation in order to obtain
GTP and valuable intermediates.
oxidative phosphorylation - disposal of the electrons released by
glycolysis and citric acid cycle. Much of the energy released in this process
can be stored as ATP.
pentose phosphate pathway - synthesis of pentoses and release of the
reducing power needed for anabolic reactions.
urea cycle - disposal of NH4+ in less toxic forms
fatty acid -oxidation - fatty acids breakdown into acetyl-CoA, to be used
by the Krebs' cycle.
gluconeogenesis - glucose synthesis from smaller percursors, to be used
by the brain.

Metabolic profiles of key tissues


Brain
Usually neurons use only glucose as energy source. Since the brain stores only a very small
amount of glycogen, it needs a steady supply of glucose. During long fasts, it becomes able to
oxidize ketone bodies.
Liver
The maintenance of a fairly steady concentration of glucose in the blood is one of the liver's
main functions. This is accomplished through gluconeogenesis and
glycogen synthesis and degradation. It synthesizes ketone bodies when acetyl-CoA is plenty. It is
also the site of urea synthesis.
Adipose tissue
It synthesizes fatty acids and stores them as triacylglycerols. Glucagon activates a hormonesensitive lipase, which hydrolizes triacylglycerols yielding glycerol and fatty acids. These are
then released into the bloodstream in lipoproteins.
Muscle
Muscles use glucose, fatty acids, ketone bodies and aminoacids as energy source. It also contains
a reserve of creatine-phosphate, a compound with a high phosphate-transfer potential that is able
to phosphorilate ADP to ATP, thereby producing energy without using glucose. The amount of
creatine in the muscle is enough to sustain about 3-4 s of exertion. After this period, the muscle
uses glycolysis, first anaerobically (since it is much faster than the citric acid cycle), and later
(when the increased acidity slows phosphofrutokinase enough for the citric acid cycle to become
non-rate-limiting) in aerobic conditions.
Kidney
It can perform gluconeogenesis and release glucose into the bloodstream. It is also responsible
for the excretion of urea, electrolytes, etc. Metabolic acidosis may be increased by the action of
the urea cycle, since urea synthesis (which takes place in the liver) uses HCO3-, thereby further
lowering blood pH. Under these circunstances, nitrogen may be eliminated by the joint action of
kidney and liver: excess nitrogen is first incorporated in glutamine by glutamine synthetase.
Kidney glutaminase then cleaves glutamine in glutamate e NH3, which the kidney immediately
excretes. This process allows nitrogen excretion without affecting blood bicarbonate levels.
Hormone control
Hormone control is mainly effected through the action of two hormones
synthesized by the pancreas: insulin and glucagon. Insulin is released by
the pancreas when blood glucose levels are high, i.e., after a meal. Insulin
stimulates glucose uptake by the muscle, glycogen synthesis, and

triacylglyceride synthesis by the adipose tissue. It inhibits gluconeogenesis


and glycogen degradation. Glucagon is released by pancreas when blood
glucose levels drop too much. Its effects are opposite those of insulin: in
liver, glucagon stimulates glycogen degradation and the absorption of
gluconeogenic aminoacids. It inhibits glycogen synthesis and promotes the
release of fatty acids by adipose tissue.

R.A #9
Overview of
Metabolism
Submitted by: Nealeth B. Nanquil
Submitted to: Professor Cyda O. Meimban

You might also like