A general overview of the major metabolic pathways

Metabolism is the set of chemical reactions that occur in a cell, which enable it to keep
living, growing and dividing. It is the sum total of all chemical reactions which occur in the
cell. The consideration of energy flows within the cell provides an excellent conceptual
framework for the entire subject of cell metabolism.

Metabolic processes are usually classified as:

 catabolism - obtaining energy and reducing power from nutrients (the breakdown of
nutrients to obtain energy).
 anabolism - production of new cell components, usually through processes that require
energy and reducing power obtained from nutrient catabolism.
METABOLIC PATHWAYS
Metabolic pathways (kreb's cycle, electron transport chain and glycolisis) can be regulated
by the help of energy that is moving between the pathways during the metabolic activities.
Metabolic pathways are all about the processes occurring with in the cell for energy
production. They have an active molecule called ATP (adenosine tri phosphate). It has to
move from one form to another during these activities. Metabolic pathways are very
regular and they are working at a proper speed all the time. They are self regulated
pathways. (M.P. is a cycle of energy production and conversion during which ATP
moves or is converted from one form to another. It keeps the balance of energy
production).

Metabolic pathways are to be regulated by themselves. It is the energy production which is

accountable for keeping the balance. Another thing which has an impact on the process of
regulation of metabolic pathways is the starting reactant and catalyst. All the time, they
have easily available catalysts and starting reactants. They act like a pusher to give impetus
to the whole pathway. Once it gets started then it is not a big thing to go on. It will keep in
motion by itself. No doubt, it is also a pathway and can be disturbed by various actions but
it recovers it self very actively.

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.

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 α-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.

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.