GENS 212 - Biochemistry

Research Activity #10

Overview of Metabolism

Submitted By:

Nool, Kimberlee Ced G.

1st Yr – BS Nursing
Metabolism is the set of chemical rections that occur in a cell, which enable it to
keep living, growing and dividing. Metabolic processes are usually classified as:

catabolism - obtaining energy and reducing power from nutrients.

anabolism - production of new cell components, usually through processes that

require energy and reducing power obtained from nutrient catabolism.

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 β-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 pathways interact in a complex way in order to allow an adequate
regulation. This interaction includes the enzymatic control of each pathway, each
organ's metabolic profile and hormone control.
Enzymatic control of metabolic pathways

Regulation of glycolysis

Metabolic flow through glycolysis can be regulated at three key points:

 hexokinase: is inhibited by glucose-6-P (product inhibition)

 phosphofructokinase: is inhibited by ATP and citrate (which signals the
abundance of citric acid cycle intermediates). It is also inhibited by H+,
which becomes important under anaerobiosis (lactic fermentation produces
lactic acid, resulting on a lowering of the pH ). Probably this mechanism
prevents the cell from using all its ATP stock in the phosphofrutokinase
reaction, which would prevent glucose activation by hexokinase. It is
stimulated by its substrate (fructose-6-phosphate), AMP and ADP (which
signal the lack of available energy), etc.
 pyruvate kinase: inhibited by ATP and acetyl-CoA
Regulation of gluconeogenesis

Flow is regulated in the gluconeogenesis-specific reactions. Pyruvate carboxilase is

activated by acetyl-CoA, which signals the abundance of citric acid
cycle intermediates, i.e., a decreased need of glucose.

Regulation of the citric acid cycle

The citric acid cycle is regulated mostly by substrate availability, product
inhibition and by some cycle intermediates.

 pyruvate dehydrogenase: is inhibited by its products, acetyl-CoA and

NADH
 citrate synthase: is inhibited by its product, citrate. It is also inhibited by
NADH and succinyl-CoA (which signal the abundance of citric acid
cycle intermediates).
 isocitrate dehydrogenase and a-ketoglutarate dehydrogenase: like citrate
synthase, these are inhibited by NADH and succinyl-CoA. Isocitrate
dehydrogenase is also inhibited by ATP and stimulated by ADP. All
aforementioned dehydrogenases are stimulated by Ca2+. This makes sense in
the muscle, since Ca2+ release from the sarcoplasmic reticulum triggers
muscle contraction, which requires a lot of energy. This way, the same
"second messenger" activates an energy-demanding task and the means to
produce that energy.
Regulation of the urea cycle

Carbamoyl-phosphate sinthetase is stimulated by N-acetylglutamine, which signals

the presence of high amounts of nitrogen in the body.

Regulation of glycogen metabolism

Liver contains a hexokinase (hexokinase D or glucokinase)with low affinity for
glucose which (unlike "regular" hexokinase) is not subject to product inhibition.
Therefore, glucose is only phosphrylated in the liver when it is present in very high
concentrations (i.e. after a meal). In this way, the liver will not compete with other
tissues for glucose when this sugar is scarce, but will accumulate high levels of
glucose for glycogen synthesis right after a meal.

Regulation of fatty acids metabolism

Acyl-CoA movement into the mitochondrion is a crucial factor in regulation.

Malonyl-CoA (which is present in the cytoplasm in high amounts when metabolic
fuels are abundant) inhibits carnitine acyltransferase, thereby preventing acyl-CoA
from entering the mitochondrion. Furthermore, 3-hydroxyacyl-CoA dehydrogenase
is inhibited by NADH and thiolase is inhibited by acetyl-CoA, so that fatty acids
wil not be oxidized when there are plenty of energy-yielding substrates in the cell.
Regulation of the pentose phosphate pathway

Metabolic flow through the pentose phosphate pathway is controled by the activity
of glucose-6-phosphate dehydrogenase, which is controlled by NADP+ availability.

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

hormone-sensitive 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.

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