Metabolic Pathways.
Enzymes.
Most of the chemical reactions in the body, if carried out in a test tube,
with only reactants and product present, would proceed at very slow rates,
because they have large activation energies.
To achieve the fast reaction rates observed in living organisms,
catalysts must lower the activation energies.
These particular catalysts are called enzymes.
Enzymes are protein molecules, so an enzyme can be defined as a protein catalyst, in most cases.
To function, an enzyme must come into contact with reactants, which are called substrates,
in the case of enzyme mediated reactions.
The substrate becomes bound to the enzymes forming a enzyme-substrate complex,
which then breakdown to release products and enzymes.
The reaction between enzymes and substrate can be written:
Note : In the equation the right arrow reads as —>
S(substrate) + E(enzyme) —> ES(enzyme substrate complex) —> P(product) + E(Enzyme).
At the end of the reaction, the enzyme is free to undergo the same reaction,
with additional substrate molecules.
The overall effect is to accelerate the conversion of a substrate into product,
with the enzyme acting as a catalyst.
An enzyme increases both the forward and reverse rates of a reaction,
and thus does not change the chemical equilibrium that is finally reached.
The interaction between substrate and enzyme has all the characteristics,
for the binding of a ligand to a binding site on a protein -
specificity, affinity, competition, and saturation.
The region of the enzyme the substrate binds to is known as the enzyme’s active site,
or binding site.
The shape of the enzyme in the region of the active site,
provides the basis for the enzyme’s chemical specificity.
Two models have been proposed to describe the interaction of an enzyme with its substrates.
In one, the enzyme and substrates fit together in a ‘lock and key’ configuration.
In another model, the substrate itself reduces a shape change in the active site of the enzyme,
which results in a highly specific binding interaction, (induced-fit model), a good example of the
dependence of function on structure at the protein level.
A typical cell expresses several thousand different enzymes,
each capable of catalysing a different chemical reaction.
Enzymes are generally named by adding the suffix -ase to the name of either the substrate,
or the type of reaction the enzyme catalyses.
For example, the reaction in which carbonic acid is broken down into carbon dioxide and water,
is catalysed by the enzyme, carbonic anhydrase.
The catalytic activity of an enzyme can be extremely large.
For example, one molecule of carbonic anhydrase can catalyse the conversion,
of about 100 thousand substrate molecules to products in one second.
Characteristics of enzymes.
-An enzyme undergoes no net chemical change as a consequence of the reaction it catalyses.
-The binding of substrate to an enzymes active site has all the characteristics - chemical specificity,
affinity, competition, and saturation - of a ligand binding to a protein.
-An enzyme increases the rate of a chemical reaction, but does not cause a reaction to occur,
that would not occur in its absence.
-Some enzymes increase both forward and reverse rates of a chemical reaction,
and thus do not change the chemical equilibrium finally reached.
They only increase the rate at which equilibrium is achieved.
-An enzyme lowers the activation energy of a reaction but does not alter the amount of energy,
that is added to or released by the reactants in the course of the reaction.
Cofactors.
Many enzymes are inactive without small amounts of other substances known as cofactors.
In some cases the cofactor is a trace metal, such as magnesium, iron, zinc, or copper.
Binding of one of the metals to an enzyme alters the enzymes conformation,
so that it can interact with the substrate.
This is a form of allosteric modulation.
Because only a few enzymes molecule need to be present to catalyse,
the conversion of large amounts of substrate to product,
very small quantities of these trace metals are sufficient to maintain enzyme activity.
In other cases, the cofactor is an organic molecule,
that directly participates as one of the substrates in the reaction,
in which case the cofactor is termed a coenzyme.
Enzymes that require coenzymes catalyse reactions in which few atoms (for example, hydrogen, acetyl,
or methyl groups) are either removed or added to a substrate.
For example,
R-2H + coenzyme —> with enzyme —> R + coenzyme - 2H.
What distinguishes coenzyme from an ordinary substrate is the fate of the coenzyme.
In the example, the 2 hydrogen atoms that transfer to the coenzyme,
can then be transferred from the coenzyme to another substrate with the aid of a second enzyme.
This second reaction converts the coenzyme back to its original form,
so that it becomes available to accept two more hydrogen atoms.
A single coenzyme molecule can act over and over again to transfer molecular fragments,
from one reaction to another.
Therefore, as with metallic cofactors, only small quantities of coenzymes,
are necessary to maintain enzymatic reactions in which they participate.
Coenzymes are derived from several members of a special class of nutrients known as vitamins.
Note : N A D plus reads as NAD+
For example, the coenzymes NAD+ (nicotinamide adenine dinucleotide),
and FAD (flavin adenine dinucleotide) are derive from B vitamins niacin and riboflavin, respectively.
They have significant functions in energy metabolism by transferring hydrogen,
from one substrate to another.
Enzymes : Proteins that catalyses nearly all chemical reactions in the body.
They act on substrates (reactants) to generate products, and are not consumed by the reaction.
- Substrate binds to the active site of an enzyme (equivalent binding site of a protein).
- Mechanism of reactions may be lock-and-key or induced-fit.
Cofactors :
Modules are elements required in small concentrations by some enzymes for full activity.
- Trace metal cofactors: maintain the conformation of an enzyme’s binding site,
so that it is able to bind substrate.
- Coenzymes derived from vitamins : transfer small groups of atoms from one substrate to another:
regenerated in the course of these reactions to function over and over again.
Regulation of enzyme-mediated reactions.
The rate of an enzyme-mediated reaction depends on substrates concentration,
and activity of the enzyme, that catalysis till reaction.
Body temperature is normally nearly constant,
so changes in temperature do not directly alter the rates of metabolic reactions.
Increases in body temperature can occur during a fever, however,
and around muscle tissue during exercise.
Such increases in temperature increase the rate of all metabolic reactions,
including enzymes catalysed ones, in the affected tissues.
Substrate concentration.
Substrate concentration may be altered as a result of factors,
that alter the supply of a substrate from outside a cell.
For example, there may be changes in diet or the rate of substrate absorption from the intestinal tract.
Inter cellular substrate concentration can also be altered by cellular reactions,
that either utilise the substrate, and thus reduce the concentration, or synthesise the substrate,
and thereby increase its concentration.
The rate of a enzyme mediated reaction increases as the substrate concentration increases,
until it reaches a maximal rate,
which remains constant despite further increases in substrate concentration.
The maximal rate is reached when the enzyme becomes saturated with substrate - that is,
when the active binding site of every enzyme molecule is occupied by a substrate molecule.
Enzyme concentration.
At any substrate concentration, including saturating concentration,
the rate of an enzyme mediated reaction can be increased by increasing the enzymes concentration.
In most metabolic reactions, the substrate concentration is much greater than the concentration,
of an enzyme available to catalyse the reaction.
Therefore, if the number of enzymes molecules is doubled,
twice as many substrate molecules will be converted into product.
Certain reactions proceed faster in some cells then in others,
because more enzyme molecules are present.
To change the concentration of an enzyme, either the rate of enzyme synthesis,
or the rate of enzyme breakdown must be altered.
Because enzymes are proteins, this involves changing the rates of protein synthesis or breakdown.
Enzyme activity.
In addition to changing the rate of enzyme mediated reactions by changing the concentration,
of either substrate or enzyme, the rate can be altered by changing enzyme activity.
A change in enzyme activity occurs when either allosteric or covalent modulation,
alters the properties (for example, the structure) of the enzyme’s active site.
Such modulation alters the rate at which the binding site converts substrate to product,
the affinity of the binding site for substrate, or both.
If the substrate concentration is less than the saturating concentration,
the increased affinity of the enzyme’s binding sites results in an increased number of active sites,
bound to substrate and, consequently, a increase in the reaction rate.
The regulation of metabolism through the control of enzyme activity is an extremely complex process,
because in many cases, more than one agent can alter the activity of an enzyme.
The modulator molecules that allosterically alter enzyme activities,
may be product molecules of other cellular reactions.
The result is that the overall rates of metabolism can adjust to meet various metabolic demands.
In contrast, covalent modulation of enzyme activity is mediated by protein kinase enzymes,
that are themselves activated by various chemical signals the cell receives from,
for example, a hormone.
In summary:
Rates of enzyme mediated reactions can be increased by,
- increase in temperature.
- increase in substrate concentration.
- increase in enzyme concentration.
- increase in enzyme activity.
Enzyme activity : altered by allosteric or covalent activation or inhibition :
a given enzyme may have several regulatory sites.
Multi enzyme reactions.
The sequence of enzyme mediated reactions leading to the formation of a particular product,
is known as a metabolic pathway.
For example, the 19 reactions that breakdown glucose, to carbon dioxide and water,
constitute the metabolic pathway for glucose catabolism,
a key homeostatic process that regulates energy availability in all cells.
Each reaction produces only a small change in the structure of the substrate.
By such a sequence of small steps, a complex chemical structure,
such as glucose can be broken down to the relatively simple molecular structures,
carbon dioxide and water.
Consider a metabolic pathway containing four enzymes (e1, e2, e3 and e4),
and leading from an initial substrate A, to the end product E,
through a series of intermediates B, C and D.
A —> B —> C —>D —>E, mediated by enzymes e1, e2,e3 and e4.
The last reaction is irreversible, the others are reversible.
By mass action, increasing the concentration of A, will lead to an increase in concentration of B,
(provided e1 is not already saturated with substrate),
and so on until eventually there is an increase in the concentration of E.
Because different enzymes have different concentrations and activities,
it would be extremely unlikely that the reaction rates of all these steps would be exactly the same.
Consequently, one step is likely to be slower than all the others.
This step is known as the rate limiting reaction in a metabolic pathway.
None of the reactions that occur later in the sequence, including the formation of the end product,
can proceed more rapidly than the rate limiting reaction, in the metabolic pathway.
None of the reactions that occur later in the sequence, including the formation of end product,
can proceed more rapidly than the rate limiting reaction,
because their substrates are supplied by the previous steps.
By regulating the concentration or activity of the rate limiting enzyme,
the rate of flow through the whole pathway can be increased or decreased.
Thus, it is not necessary to alter all the enzymes in a metabolic pathway,
to control the rate at which the end product is produced.
Rate limiting enzymes are often the sites of allosteric or covalent regulation.
For example, if the enzyme e2 is rate limiting in the pathway, and if the end product E inhibits the
activity of e2, end-product inhibition occurs.
As the concentration of the product increases,
the inhibition of further product formation increases.
Such inhibition, which is a form of negative feedback, frequently occurs in synthetic pathways,
in which the formation of an end product is effectively shutdown, when it is not being utilised.
This prevents unnecessary excessive accumulation of the end product,
and contributes to the homeostatic balance of the product.
Control of enzyme activity can be critical for reversing a metabolic pathway.
Consider the pathway we have been discussing,
ignoring the presence of end product inhibition of enzyme e2.
This pathway consists of three reversible reactions mediated by e1, e2 and e3,
followed by an irreversible reaction mediated by enzyme e4.
E can be converted to D, however, if the reaction is coupled to the simultaneous breakdown,
of a molecule that releases large quantities of energy.
In other words, an irreversible step can be reversed by an alternative route,
using a second enzyme and its substrate to provide the large amount of required energy.
A —> B—>C—>D—>E, mediated by e1, e2, e3 and e4.
D to E is mediated by the enzyme e4.
X to Y is mediated by the enzyme e5.
The flow from A to B, B to C, and C to D is bidirectional.
The direction of flow through the pathway can be regulated,
by controlling the concentration and/or activities of e4 and e5.
If e4 is activated and e5 is inhibited, the flow will proceed from A to E,
whereas inhibition of e4 and activation of e5 will produce flow from E to A.
Another situation involving the differential control of several enzymes arises,
when there is a branch in a metabolic pathway.
A single metabolite C may be the substrate for more than one enzyme.
Note : A right arrow and a left arrow indicating a bidirectional flow reads as A —> <— B.
A —> <— B --> <— C, mediated by enzymes e1 and e2.
This has two branches,
C—> <— D —> <— E mediated by enzymes e3 and e4.
C —> <— F —> <— G mediated by enzymes e5 and e6.
Altering the concentration and/or activities of e3 and e5,
regulates the flow of metabolite C through the two branches of the pathway.
Considering the thousands of reactions that occur in the body, and the permutations and combinations, of possible control points, the overall result is staggering.
We will only consider,
1. the overall characteristics of the pathways by which cells obtain energy; and,
2. the major pathways by which carbohydrates, fats and proteins are broken down and synthesised.
In summary:
- Metabolic pathway: sequence of enzyme mediated reactions,
leading to the formation of a particular product.
- Rate limiting reaction: enzyme catalysed step that determines rate of product formation,
in a metabolic pathway.
- End product inhibition: occurs when the end product of a metabolic pathway,
acts as a modulator molecule, inhibiting the rate limiting enzyme’s activity.
- Many metabolic pathways are reversible.
Metabolic pathways.
The functioning of the cell depends upon its ability to extract and use the chemical energy,
in the organic molecules.
For example, when, in the presence of oxygen, a cell breaks down glucose to yield carbon dioxide,
and water, energy is released.
Some of this energy is in the form of heat, but a cell cannot use heat energy to perform its functions.
The reminder of this energy is transferred to the nucleotide adenosine triphosphate (ATP),
comprised of an adenine molecule, a ribose molecule and three phosphate groups.
ATP is the primary molecule that stores energy transferred from the breakdown of carbohydrates,
fats, and protein.
Energy released from organic molecules is used to add phosphate groups to molecules of adenosine.
This stored energy can be released upon hydrolysis.
Inorganic phosphorus reads as ‘Pi’.
ATP + H2O —> ADP + Pi + H+ + energy.
The products of the reaction are adenosine diphosphate (ADP), inorganic phosphate (Pi) and H+.
Among other things, the energy derived from the hydrolysis of ATP is used by cells for:
- the production of force and muscle movement, as in muscle contraction.
- active transport of molecules across membranes.
- synthesis of organic molecules used in cell structures and functions.
Cells use 3 distinct but linked metabolic pathways to transfer the energy released,
from the breakdown of nutrient molecules to ATP.
They are known as,
1. Glycolysis.
2. The Krebs cycle.
3. Oxidative phosphorylation.
We will describe the major characteristics of these three pathways,
including the location of the pathway enzymes in the cell,
the relative contribution of each pathway to ATP production, the sites of carbon dioxide formation,
and oxygen utilisation, and the key molecules that enter and leave each pathway.
Glycolysis operates only in carbohydrates.
All the categories are macromolecular nutrients, - carbohydrates, fats and proteins -
contribute to the ATP production via the Krebs cycle and oxidative for phosphorylation.
Glycolysis can occur in either the presence or absence of oxygen,
whereas both the Krebs cycle and oxidative phosphorylation require oxygen.
Cellular Energy Transfer.
Glycolysis.
Glycolysis in Greek means breakdown of sugar.
Glycolysis is a pathway that partially categories carbohydrates primarily glucose.
It consists of 10 enzymatic reactions that breakdown a six carbon molecule of glucose,
into three carbon molecules of pyruvate, the ionised form of pyruvic acid.
The reactions provide a net gain of 2 molecules of ATP and four atoms of hydrogen,
two transferred to NAD+ and two released hydrogen ions.
The coenzyme NAD+ is involved in the reaction.
Coenzyme are derived from several members of a special class of nutrients known as vitamins.
Example, the coenzyme NAD+(nicotinamide adenine dinucleotide) an FAD (flavin adenine dinucleotide),
are derived from B vitamins, niacin and riboflavin respectively.
They have significant functions in energy metabolism by transferring hydrogen,
from one substrate to another.
Glucose + 2 ADP + 2 Pi + 2NAD+ —> 2 pyruvate +2 ATP + 2 NADH + 2 H+ + 2 H2O.
Reaction 1.
Glucose to glucose 6-phosphate.
ATP is converted to ADP.
Reaction 2 .
Glucose 6-phosphate to fructose 6-phosphate.
Reaction 3.
Fructose 6-phosphate to fructose 1,6-biphosphate.
ATP is converted to ADP.
Reaction 4a.
Fructose 1,6-biphosphate to dihydroxyacetone.
Reaction 4b.
Fructose 1,6-biphosphate to 3 phosphoglyceraldehyde.
Reaction 5.
Dihydroxyacetone to 3 phosphoglyceraldehyde.
Reaction 6.
3 phosphoglyceraldehyde to 1,3-Biphosphoglycerate.
Inorganic phosphate is added.
NAD+ becomes NADH + H+.
Reaction 7.
1,3-Biphosphoglycerate to 3- phosphoglycerate.
Reaction 8.
3- phosphoglycerate to 2- phosphoglycrerate.
Reaction 9.
2- phosphoglycrerate to phosphoenolpyruvate.
H2O is released.
Reaction 10.
Phosphoenolpyruvate to pyruvate.
ADP is converted to ATP.
Now there are two branches.
Branch 11a.
Pyruvate to lactate.
NADH + H+ to NAD+.
Branch 11b.
Pyruvate to Krebs cycle.
These 10 reactions, non of which utilities molecular oxygen, takes place in the cytosol.
All the intermediates between glucose and the end product pyruvate,
contain one or more ionised phosphate groups.
Plasma membranes are impermeable to such highly ionised molecules ;
therefore these molecules remain trapped within the cell.
The early steps in glycolysis (reactions 1 and 3) each use, rather than produce,
one molecule of ATP to form phosphorylated intermediates.
In addition reaction 4, splits a six carbon intermediate into two 3 carbon molecules.
Reaction 5 converts one of these 3 carbon molecules into the other.
Thus, at the end of reaction 5, we have two molecules of 3 phosphoglyceraldehyde,
derived from one molecule of glucose.
The first formation of ATP in glycolysis occurs during reaction 7,
in which a phosphate group is transferred to ADP to form ATP.
Because, two intermediates exists at this point, reaction 7 produces two molecules of ATP,
one from each intermediate.
In this reaction, the mechanism for forming ATP is known as substrate level phosphorylation,
because the phosphate group is transferred from a substrate molecule to ADP.
A similar substrate level phosphorylation of ADP occurs during reaction 10,
in which again two molecules of ATP are formed.
Thus reactions 7 and 10 generate a total of 4 molecules of ATP for every molecule of glucose,
entering the pathway.
There is a net gain however, of only two molecules of ATP during glycolysis,
because two molecules of ATP are used in reaction 1 and 3.
Regardless of the presence or absence of oxygen, much of the end product of glycolysis, pyruvate,
is reduced to lactate (the ionised form of lactic acid), by a single enzyme mediated reaction.
In this reaction two hydrogen atoms derived from NADH++ H+ are transferred,
to each molecule of pyruvate to form lactate, and NAD+ is regenerated.
These hydrogen’s were originally transferred to NAD+ during reaction 6 of glycolysis,
so the coenzyme NAD+ shuttles hydrogen between the two reactions during glycolysis.
The overall reaction for the breakdown of glucose to lactate is,
Glucose + 2ADP + 2Pi —> 2 Lactate + 2ATP + 2H2O.
The remainder of the pyruvate is not converted to lactate,
but instead enters the Krebs cycle to be broken down to carbon dioxide.
The hydrogens of NADH are transferred to oxygen during oxidative phosphorylation,
regenerating NAD+ and producing H2O.
In most cells, the amount of ATP produced by glycolysis from one molecule of glucose,
is much less when the amount formed by the other two ATP generating pathways -,
the Krebs cycle and oxidative phosphorylation.
In special cases, however glycolysis supplies most - or even all - of a cell’s ATP.
For example, erythrocytes contain the enzymes for glycolysis but have no mitochondria,
which are required for the other pathways.
All of their ATP production occurs, therefore, by glycolysis.
Also, certain types of skeleton muscles contain considerable amounts of glycolytic enzymes,
but few mitochondria.
During intense muscle activity, glycolysis provides most of the ATP in the cells,
and is associated with the production of large amount of lactate.
Despite these exceptions, most cells don’t have sufficient concentration of glycolytic enzymes,
or enough glucose to provide by glycolysis alone,
the high rates of ATP production necessary to meet their energy requirements.
Some of the lactate that is formed during glycolysis is released into the blood,
and taken up by the heart, brain and other tissues where it is converted back to pyruvate,
and used as a energy source.
This process has been termed as the inter cellular lactate shuttle.
Another portion of the secreted lactate is taken up by the liver,
where it is used as a precursor for the formation of glucose, which is then released into the blood,
where it becomes available as an energy source for all cells.
The latter reaction is particularly important during periods in which energy demands are high,
such as during exercise.
Finally, some of the lactate produced can be oxidised back to pyruvate and used by those cells.
Other carbohydrates such as fructose, derived from the disaccharide sucrose(table sugar),
and galactose, from the disaccharide lactose (milk sugar), can also be catabolised by glycolysis,
because these carbohydrates are broken down into several of the intermediates,
that participate in the early portion of the glycolytic pathway.
Krebs cycle.
The Krebs cycle is named in honour of Hans Krebs,
who worked out the intermediate steps in the pathway.
The Krebs cycle is the second of the three pathways involved in nutrient catabolism,
and ATP production.
It utilises molecular fragments formed during carbohydrate, protein and fat breakdown.
It produces carbon dioxide, hydrogen atoms (half of which are bound to coenzymes),
and small amounts of ATP.
The enzymes for this pathway are located in the inner mitochondria compartment, the matrix.
Note : C o A reads as CoA.
The primary molecule entering at the beginning of the Kerbs cycle is acetyl coenzyme (acetyl CoA).
Coenzyme A (CoA) is derived from the B vitamin pantothenic acid,
and functions primarily to transfer acetyl groups, which contain two carbons,
from one molecule to another.
These acetyl groups come either from pyruvate - an end product of glycolysis - ,
or from the breakdown of fatty acids and some amino acids.
Pyruvate, upon entering mitochondria from the cytosine, is metabolised to acetyl CoA and CO2.
This reaction produces the first molecule of CO2 formed thus far in the pathways of nutrient catabolism,
and the reaction also transfers hydrogen atoms to NAD+.
The Krebs cycle begins with the transfer of the acetyl group of acetyl CoA to the four carbon molecule,
oxaloacetate to form the six-carbon molecule citrate.
At the 3rd step in the cycle, a molecule of CO2 is produced - and again at the 4th step.
Therefore, 2 carbon atoms entered the cycle as part of the acetyl group attached to CoA,
and two carbon atoms (although not the same ones) have left in the form of CO2.
The oxygen that appears in the CO2 , is derived not from molecular oxygen,
but from the carboxyl groups of Krebs cycle intermediates.
In the remainder of the cycle, 4 carbon molecule formed in reaction 4 is modified,
through a series of reactions to produce a four-carbon molecule oxaloacetate,
which becomes available to accept another acetyl group and repeat the cycle.
In addition to producing carbon dioxide, intermediates in the Krebs cycle generate hydrogen atoms,
most of which are transferred to the coenzyme NAD+ and FAD to form NADH and FADH2.
These hydrogens will be transferred from the coenzymes, along with the free H+,
to oxygen in the next stage of nutrient metabolism - oxidative phosphorylation.
Because oxidative phosphorylation is necessary for regeneration,
of the hydrogen free form of these coenzymes,
the Krebs cycle can operate only under aerobic conditions.
There is no pathway in the mitochondria that can remove the hydrogen,
from these coenzymes under anaerobic conditions.
So far we have said nothing of how the Krebs cycle contributes to the formation of ATP.
In fact, the Krebs cycle directly produces only one high energy nucleotide triphosphate.
This occurs during the reaction 5 in which the inorganic phosphate,
is transferred to guanosine diphosphate (GDP) to form guanosine triphosphate (GTP).
The hydrolysis of GTP, like that of ATP, can provide energy for some energy requiring reactions.
In addition, the energy in GTP can be transferred to ATP by the reaction,
GTP + ADP —> <— GDP + ATP.
The formation of ATP from GTP is the only mechanism by which ATP is formed in the Krebs cycle.
The reason why Krebs cycle is very important is that the hydrogen atoms transferred to co-enzymes, during the cycle (plus the free hydrogen ions generated) are used in the next pathway,
oxidative phosphorylation, to form large amounts of ATP.
The net result of the catabolism of one acetyl group from acetyl CoA by way of Krebs cycle,
can be written as :
Acetyl CoA + 3 NAD+ + FAD + GDP + Pi +2 H2O —>
2 CO2 + CoA + 3NADH + 3H+ +GTP.
Characteristics of the Krebs cycle.
- Entering substrate : Acetyl Coenzyme A - Acetyl groups derived from pyruvate, fatty acids,
and amino acids.
Some intermediates derived from amino acids.
- Enzyme location : Inner compartments of mitochondria (the mitochondrial matrix).
- ATP production : One GTP formed directly, which can be converted to ATP.
Operates only under aerobic conditions,
even though molecular oxygen is not used directly in this pathway.
- Coenzyme production :
3NADH + 3H+ and 2FAD2
- Final products : 2CO2 for each molecule of Coenzyme A entering pathway.
Some intermediate used to synthesise amino acids and other organic molecules,
required for special cell functions.
- Net reaction :
Acetyl CoA + 3 NAD+ + FAD + GDP + Pi + 2H2O.
—> 2 CO2 + CoA + 3 NADH + 3 H+ + FADH2 + GTP.
Oxidative Phosphorylation.
Oxidative phosphorylation provides the third, and quantitatively most important,
mechanism by which energy derived from nutrient molecules can be transferred to ATP.
The basic principle behind this pathway is simple:
The energy transferred to ATP is derived from the energy released,
when hydrogen ions combine with molecular oxygen to form water.
The hydrogen ions come from the NADH + H+ and FADH2 .
Coenzymes generated by the Krebs cycle, by the metabolism of fatty acids - to a much lesser extent -
during glycolysis.
The net reaction is
half O2 + NADH + H+ —> H2O + NAD+ + energy.
Unlike the enzymes of the Krebs cycle, which are soluble enzymes in the mitochondrial matrix,
the proteins that mediate oxidative phosphorylation are embedded in the mitochondrial memory.
The proteins for oxidative phosphorylation can be divided into two groups:
1. Those that mediate the series of reactions that cause the transfer of hydrogen ions,
to molecular oxygen.
2. Those that couple the energy released by these reactions to the synthesis of ATP.
Some of the first group of proteins contain iron and copper cofactors, and are known as cytochromes,
(because in pure form they are brightly coloured).
Their structure resembles the red iron containing haemoglobin molecule,
which binds oxygen in red blood cells.
The cytochromes and associated proteins form the components of the electron transport chain,
in which two electrons from each hydrogen atoms are initially transferred either from NADH + H+,
or FADH2 to one of the elements in this chain.
These electrons are then successfully transferred to other compounds in the chain,
often to or from iron or copper ion, until the electrons are finally transferred to molecular oxygen,
which then combines with hydrogen ions (protons) to form water.
These hydrogen ions, like the electrons, come from free hydrogen ions,
and the hydrogen bearing coenzymes, having been released early in the transport chain,
when the electrons from the hydrogen atoms were transferred to the cytochromes.
Importantly, in addition to transferring the coenzyme hydrogens to water,
this process regenerates the hydrogen free form of the coenzymes,
which then become available to accept two or more hydrogens from intermediates in the Krebs cycle,
glycolysis, or fatty acid pathway.
At certain steps along the electron-transport chain, small amounts of energy is released.
As electrons are transferred from one protein to another along the electron-transport chain,
some of the energy released is used by the cytochromes to pump hydrogen ions,
from the matrix into the inter membrane space -
the compartment between the inner and outer mitochondrial membranes.
This creates a source of potential energy,
in the form of hydrogen-ion-concentration gradient across the membrane.
Solutes such as hydrogen ions move - or diffuse - along concentration gradients,
but the presence of a lipid bilayer blocks the diffusion of most water soluble molecules and ions.
Embedded in the inner mitochondria membrane, however, is an enzyme called ATP synthase.
This enzyme forms a channel in the inner mitochondria membrane,
allowing the hydrogen ions to flow back to the matrix side, a process that is known as chemiosmosis.
In the process the energy of the concentration gradient is converted to chemical bond energy,
by ATP synthase, which catalyses the formation of ATP from ADP and Pi.
FADH2 enters the electron transport chain at the point beyond that of NADH,
and therefore doesn’t contribute quite as much to chemiosmosis.
The processes associated with chemiosmosis are not perfectly stoichiometric, however,
because some of the NADH that is produced in glycolysis and the Krebs cycle,
is used for other cellular activities, such as the synthesis of organic molecules.
Also, some of the hydrogen ions in the mitochondria are used for other activities,
besides the generation of ATP.
Therefore the transfer of electrons to oxygen typically produces on average,
approximately 2.5 and 1.5 molecules of ATP for each molecule of NADH + H+ and FADH2.
In summary, most ATP formed in the body is produced during oxidative phosphorylation,
as a result of processing hydrogen atoms that originated from the Krebs cycle,
during the breakdown of carbohydrates, fats and proteins.
The mitochondria, where the oxidative phosphorylation and the Krebs-cycle reactions occur,
are thus considered the powerhouses of the cell.
In addition, most of the oxygen we breathe is consumed within these organelles,
and most of the carbon dioxide we exhale is produced within them as well.
Characteristics of oxidative phosphorylation.
Entering substrates:
Hydrogen atoms obtained from NADH + H+ and FADH2 formed
1. During glycolysis.
2. By the Krebs cycle, during the breakdown of pyruvate and amino acids and,
3. During the breakdown of fatty acids.
Molecular oxygen.
Enzyme location:
Inter mitochondrial membrane.
ATP production:
2 to 3 ATP formed from each NADH + H+ .
1 to 2 ATP formed from each FADH.
Final products:
H2O One molecule for each pair of hydrogens entering pathway.
Net reaction:
Half O2 + NADH + H+ + 3ADP + 3 Pi —>
H2O + NAD+ + 3ATP.
Review.
Glycolysis:
Cytosolic reactions that breakdown glucose into pyruvate and lactate, H+, NADH, water and ATP.
H+ are then transferred either to NAD+ which then transfers them to pyruvate to form lactate,
thereby regenerating the original coenzyme molecule, or to the oxidative phosphorylation pathway.
ATP forms by substrate level phosphorylation, a process in which a phosphate group,
is transferred from a phosphorylated metabolic intermediate directly to ADP.
Krebs cycle:
Mitochondrial pathway that utilises breakdown products of organic macromolecules to yield CO2,
ATP and H+.
Acetyl coenzyme A derived partly from all three types of nutrient macromolecules;
is the major substrate entering the Krebs cycle.
During one cycle of the Krebs cycle, 2 CO2 are produced,
and four pairs of hydrogen atoms are transferred to coenzymes.
Oxidative Phosphorylation:
Process occurring on inner mitochondrial membranes in which ATP is formed from ADP and Pi,
using energy released when O2 combines with H+to form water.
H+ is derived from glycolysis, Krebs cycle, and breakdown of fatty acids.
H+ are delivered, most bound to coenzymes, to the electron transport chain.
Electron transport chain:
Regenerates hydrogen free forms of coenzymes NAD+ and FAD by transferring the H+ to O2.
Reactions of the electron transport chain produces a H+gradient,
across the inner mitochondrial membrane.
The flow of H+ back across the membrane provides energy for ATP synthesis.
Carbohydrate, Fat, and Protein Metabolism.
We have discussed the three pathways by which energy is transferred to ATP.
We will discuss how each of these energy yielding nutrient molecules, - carbohydrates, fats,
and proteins - enters the ATP generating pathways.
We will also discuss the synthesis of these molecules and the pathways and restrictions governing,
how breakdown products of one class can be used in the synthesis of a different class.
These anabolic pathways are also used to synthesise molecules,
that have functions other than the storage and release of energy.
For example, with the addition of few enzymes,
the pathway for fat synthesis is also used for the synthesis of phospholipids formed in membranes.
Carbohydrate metabolism.
Carbohydrate catabolism.
We have discussed the breakdown of glucose to pyruvate or lactate by way of the glycolytic pathway,
and the metabolism of pyruvate to carbon dioxide and water by way of the Krebs cycle,
and oxidative phosphorylation.
The amount of energy released during the catabolism of glucose to carbon dioxide and water,
is 686 kcal/mol, which is 686 kilo calories per mole.
C6H12O6+6O2 —> 6H2O + 6CO2 + 686 kcal/mol.
About 40% of this energy is transferred to ATP.
A net gain of 2 ATP molecules occurs by substrate level phosphorylation during glycolysis,
and 2 more are formed during the Krebs cycle from GTP,
one from each of the two molecules of pyruvate entering the cycle.
The majority of ATP molecules glucose catabolism produces - unto 34 ATP per molecule -
form during oxidative phosphorylation from the hydrogens generated at various steps,
during glucose breakdown.
Because in the absence of oxygen only 2 molecules of ATP,
can form from the breakdown of glucose to lactate,
the evolution of aerobic metabolic pathways greatly increased the amount of energy,
available to a cell from glucose catabolism.
The evolution of aerobic metabolic pathways greatly increased the amount of energy,
available to a cell from glucose metabolism.
For example, if a muscle cell consumed 38 molecules of ATP during a contraction,
this amount of ATP could be supplied by the breakdown of one molecule of glucose,
in the presence of oxygen or 19 molecules of glucose under anaerobic conditions.
However, although only 2 molecules of ATP are formed,
per molecule of glucose under anaerobic conditions,
large amounts of ATP can still be supplied by the glycolytic pathway,
if large amounts of glucose are broken down to lactate.
This is not an efficient utilisation of nutrients, but it does permit continued ATP production,
under conditions in which oxygen becomes limiting, such as occurring during intense exercise.
Glycogen storage.
A small amount of glucose can be stored in the body to provide a reserve supply for use,
when glucose is not been absorbed into the blood from the small intestine.
It is stored as polysaccharide glycogen, mostly in skeletal muscles and the liver.
The enzymes for both glycogen synthesis and glycogen breakdown are located in the cytosol.
The first step in glycogen synthesis,
the transfer of phosphate molecule from a molecule of ATP to glucose,
forming a glucose 6-phosphate, is the same as the first step in glycolysis.
Thus glucose 6-phosphate can be broken down to pyruvate or used to form glycogen.
Different enzymes synthesise and breakdown glycogen.
The existence of two pathways containing enzymes,
that are subject to both covalent and allosteric modulation provides a mechanism,
for regulating the flow between glucose and glycogen.
When an excess of glucose is available to a liver or muscle cell,
the enzymes in the glycogen synthesis pathway are activated,
and the enzyme breaks down glycogen is simultaneously inhibited.
This combination leads to the net storage of glucose in the form of glycogen.
When less glucose is available, the reverse combination of enzyme stimulation occurs,
and net breakdown of glycogen to glucose 6-phosphate ensues.
This process is known as glycogenolysis.
Two paths are available to this glucose 6-phosphate.
1. In most cells, including skeletal muscle, it enters the glycolytic pathway,
where it is catabolised to provide energy for ATP formation.
2. In liver and kidney cells, glucose 6-phosphate can be converted to free glucose,
by removal of the phosphate group, and the glucose is then able to pass out of the cell into the blood,
to provide energy for other cells.
Glucose synthesis.
In addition to being formed in the liver from the breakdown of glycogen,
glucose can be synthesised in the liver, and to a lesser extent the kidneys,
from intermediates derived from the catabolism of glycerol (a sugar alcohol) and some amino acids.
This process of generating new molecules of glucose from noncarbohydrate precursors,
is known as gluconeogenesis.
The major substrate in gluconeogenesis is pyruvate, formed from lactate,
and from several amino acids during protein breakdown.
In addition, glycerol derived from the hydrolysis of triglycerides can be used to synthesise glucose,
via a pathway that does not involve pyruvate.
The pathway for gluconeogenesis in the liver and kidneys makes use of many,
but not all of the enzymes used in glycolysis, because most of these reactions are reversible.
However, reactions 1, 3 and 10 in glycolysis are irreversible, and additional enzymes are required,
therefore, to form glucose from pyruvate.
Pyruvate is converted to phosphoenolpyruvate by series of mitochondrial reactions,
in which CO2 is added to form the four carbon Krebs cycle intermediate oxloacetate,
out of the mitochondria and its conversion to phosphoenolopyruvate in the cytosol.
Phosphoenolpyruvate then reverses the steps of glycolysis back to the level of reaction 3,
in which a different enzyme from that used in glycolysis,
is required to convert fructose 1,6-biphosphate to form fructose 6-phosphate.
From this point on, the reactions are again reversible, leading to glucose 6-phosphate,
which can be converted to glucose in the liver and kidneys, or stored as glycogen.
Because energy in the form of heat and ATP generation is released during the glycolytic breakdown,
of glucose to pyruvate, energy must be added to reverse this pathway.
A total of 6 ATP are consumed in the reactions of the gluconeogenesis per molecule of glucose formed.
Many of the same enzymes are used in glycolysis and gluconeogenesis, so the questions arise:
What controls the direction of these pathways?
What conditions determine whether glucose is broken down to pyruvate,
or whether pyruvate is used to synthesise glucose?
The answers lie in the concentrations of glucose or pyruvate in the cell,
and in the control the enzymes exert in the irreversible steps in the pathway.
This control is carried out by a various hormones that alter the concentration and activities,
of these key enzymes.
For example, if the blood glucose concentration falls below normal,
certain hormones are secreted into the blood and act on the liver.
There, the hormones preferentially induce the expression of the gluconeogenic enzymes,
thereby favouring the formation of glucose.
Fat metabolism.
Fat catabolism.
Triglyceride or fat consists of three fatty acids bound to glycerol.
Fat typically accounts for approximately 80% of the energy stored in the body.
Energy content of a 70kg person.
Triglycerides :
15.6kg with an energy content of 9Kcal per gram,
and a total body energy content of 140000 Kcal, which constitutes 78% of the total energy.
Proteins :
9.5kg with an energy content of 4Kcal per gram, and a total body energy content of 38000 Kcal,
which is 21% of the total energy.
Carbohydrates:
.5kg with an energy content of 4Kcal per gram, and a total body energy content of 2000 Kcal,
which is 1% of the total energy.
Under resting conditions approximately half the energy used by muscle, the liver,
and the kidneys is derived from catabolism of fatty acids.
Although most cells store small amounts of fat,
most of the body’s fat is stored in specialised cells known as adipocytes.
Almost the entire cytoplasm of each of these cells is filled with a single, large fat droplet.
Clusters of adipose tissue, most of which is in deposits underlying the skin,
or surrounding internal organs.
The function of adipocytes is to synthesise and store triglycerides,
during periods of nutrient absorption and then,
when nutrients are not being absorbed from the small intestine,
to release fatty acids and glycerol into the blood for uptake and use by other cells,
to provide energy required for ATP formation.
We will emphasise the pathway by which most cells catabolise fatty acids,
to provide the energy for ATP synthesis,
and the pathway by which other molecules are used to synthesise fatty acids.
The breakdown of a fatty acid is initiated by linking a molecule of coenzyme A,
to the carboxyl end of a fatty acid.
The initial step is accompanied by the breakdown of ATP to AMP and two Pi .
The coenzyme A derivative of the fatty acid then proceeds through a series of reactions,
collectively known as beta oxidation.
This splits off a molecule of acetyl coenzyme A from the end of the fatty acid,
and transfers two pairs of hydrogen atoms to coenzymes, (one pair to FAD and other to NAD+).
The hydrogen atoms from the coenzymes then enter the oxidative phosphorylation pathway,
to form ATP.
When acetyl coenzyme A is split from the end of a fatty acid, another coenzyme A is added.
ATP is not required for this step, and the sequence is repeated.
Each passage through the sequence shortens the fatty acid chain by two carbon atoms,
until all the carbon atoms have transferred to coenzyme A molecules.
These molecules then leave to the production of ATP and CO2 ,
via the Krebs cycle and oxidative phosphorylation.
How much ATP is formed as a result of the total catabolism of a fatty acid?
Most fatty acids in the body contain 14 to 22 carbons, 16 and 18 being the most common.
The catabolism of one 18 carbon saturated fatty acid yields 146 ATP molecules.
The catabolism of one glucose molecule yields a maximum of 38 ATP molecules.
Thus, taking into account the difference in molecular weight of the fatty acid and glucose,
the amount of ATP formed from the catabolism of one gram of fat,
is about 2.5 times greater than the amount of ATP produced by catabolising one gram of carbohydrates.
If an average person stored most of his energy as carbohydrate rather than fat,
body weight would have to be 30% greater.
The person would consume more energy moving this weight around.
Thus a major step in energy economy occurred when animals evolved the ability to store energy as fat.
Fat synthesis.
The synthesis of fatty acids occurs by reactions that are almost the reverse of those that degrade them.
However, the enzymes in the synthetic pathway are in the cytosol,
whereas the enzymes catalysing fatty acid breakdown are in the mitochondria.
Fatty acid synthesis begins with cytoplasmic acetyl coenzyme A,
which transfers its acetyl group to form a four-carbon chain.
While repetition of this process, long chain fatty acids are built up two carbons at a time.
This accounts for the fact that all fatty acids synthesised in the body,
contain an even number of carbon atoms.
Once the fatty acids are formed, triglycerides can be synthesised by linking fatty acids,
to each of the three hydroxyl groups in glycerol, more specifically,
to a phosphorylated form of glycerol called glycerol 3-phosphate.
The synthesis of triglyceride is carried out by enzymes associated with the membranes,
of the smooth endoplasmic reticulum.
Compare to molecules produced by glucose catabolism with those required for synthesis,
of both fatty acids and glycerol 3-phosphate.
First, acetyl coenzyme A, the starting material for fatty acid synthesis, can be formed from pyruvate,
the end product of glycolysis.
Second, the other ingredients required for fatty acid synthesis - hydrogen bound coenzymes and ATP - are produced during carbohydrate catabolism.
Third, glycerol 3-phosphate can be formed from a glucose intermediate.
It should not be surprising, therefore, that much of the carbohydrate in food is broken down,
into products that can be used in the synthesis of fat and stored in adipose tissue,
shortly after its absorption from the gastrointestinal tract.
Importantly, fatty acids - or, more specifically,
the acetyl coenzyme A derived from fatty acid breakdown cannot be used,
to synthesise new molecules of glucose.
We can see the reasons for these by examining the pathways for glucose synthesis.
First, because the reaction in which pyruvate is broken down to acetyl coenzyme A,
and carbon dioxide is irreversible.
Acetyl coenzyme A cannot be converted into pyruvate,
a molecule that could lead to the production of glucose.
Second, the equivalence of two carbon atoms in acetyl coenzyme A are used to form,
two molecules of carbon dioxide during their passage through the Krebs cycle,
before reaching oxaloacetate, another take off point for glucose synthesis; therefore,
they cannot be used to synthesise net amounts of oxaloacetate.
Therefore, glucose can readily be metabolised and used to synthesise fat,
but the fatty acid portion of fat cannot be used to synthesise glucose.
Protein and amino acid metabolism.
In contrast to the complexities of protein synthesis, protein catabolism requires only a few enzymes,
collectively called proteases, to break the peptide bond between amino acids,
(a process called proteolysis).
Some of these enzymes remove one amino acid at a time from the ends of the protein chain,
whereas others break peptide bonds between specific amino acids within the chain,
forming peptides rather than free amino acids.
Amino acids can be catabolised to provide energy for ATP synthesis, and they can also provide,
intermediates for the synthesis of a number of molecules other than proteins.
Because there are 20 different amino acids, a large number of intermediates can be formed,
and there are many pathways for processing them.
A few basic types of reactions common to most of these pathways can provide an overview,
of amino acid catabolism.
Unlike most carbohydrates and fats, amino acids contain nitrogen atoms (in their amino groups),
in addition to carbon, hydrogen, and oxygen atoms.
Once the nitrogen containing amino group is removed,
the remainder of most amino acids can be metabolised to intermediates,
capable of entering either the glycolytic pathway or the Krebs cycle.
In the first reaction, oxidative deamination, the amino group gives rise to a molecule of ammonia(NH3), and is replaced by an oxygen atom derived from water to form a keto acid,
a categorical name rather than a name of a specific molecule.
The second means of removing an amino group is known as transamination,
and involves transfer of the amino group from an amino acid to a keto acid.
The keto acid to which the amino group is transferred becomes an amino acid.
Cells use the nitrogen derived from amino groups to synthesise,
other important nitrogen containing molecules,
such as purine and pyrimidine bases found in nucleic acids.
The next reaction is the oxidative deamination of the amino acid glutamic acid,
and the transamination of the amino acid alanine.
The keto acids formed are the intermediates in the Krebs cycle or glycolytic pathway (pyruvic acid).
Once formed, these keto acids can be metabolised to produce carbon dioxide and form ATP,
or they can be used as intermediates in the synthetic pathway leading to the formation of glucose.
As a third alternative, they can be used to synthesise fatty acids,
after their conversion to acetyl coenzyme A, by way of pyruvic acid.
Therefore, amino acids can be used as a source of energy,
and some can be broken down into products that can be used in the synthesis of carbohydrate and fat.
The amino that oxidative deamination produces is highly toxic to cells if allowed to accumulate.
Fortunately, it passes through plasma membranes and enters the blood, which carries it to the liver.
The liver contains enzymes that can combine two molecules of amino with carbon dioxide to form urea, which is relatively non toxic and is the major nitrogenous waste product of protein catabolism.
It enters the blood from the liver and is excreted by the kidneys into the urine.
Thus far, we have discussed mainly amino acid catabolism.
Now we turn to amino acid synthesis.
The keto acids pyruvic acid and alpha-ketoglutaric acid can be derived from the breakdown of glucose;
they can be transaminated, to form the amino acids, glutamate and alanine.
Therefore, glucose can be used to produce certain amino acids,
provided other amino acids are available in the diet to supply amino groups for transamination.
However, only 11 of the 20 amino acids can be formed by this process,
because 9 of the specific keto acids cannot be synthesised from other intermediates.
We have to obtain the 9 amino acids corresponding to these keto acids, from the food we eat.
Consequently, they are known as essential amino acids.
The amino acid pools, which consist of the body’s total free amino acids are derived from,
- ingested protein, which is degraded to amino acids during digestion in the small intestine.
- The synthesis of non essential amino acids from the keto acids derived from carbohydrates and fat.
- The continuous breakdown of body proteins.
These pools are the source of amino acids for re-synthesis of body protein,
and a host of specialised amino acid derivatives, as well as for conversion to carbohydrate and fat.
A very small quantity of amino acids and protein is lost from the body,
via the urine; skin; hair; finger nails; and in women, the menstrual fluid.
The major route for loss of amino acids is not their excretion but rather their deamination,
with the eventual excretion of the nitrogen atoms as urea in the urine.
The terms negative nitrogen balance and positive nitrogen balance refer to,
whether there is a net loss or gain respectively, of amino acids in the body over any period of time.
If any of the essential amino acids are missing from the diet, a negative nitrogen balance - that is,
loss greater than gain - always results.
The proteins that require a missing essential amino acid cannot be synthesised,
and the other amino acids that would have been incorporated into these proteins are metabolised.
This explains why a dietary requirement for protein cannot be specified,
without regard to the amino acid composition of that protein.
The highest quality proteins are found in animal products,
whereas the quality of most plant proteins is lower.
Nevertheless, it is quite possible to obtain adequate quantities of all essential amino acids,
from a mixture of plant proteins alone.
Metabolism summary.
We have discussed the metabolism of the three major classes of organic molecules.
We will review, how each class is related to the others and to the process of synthesising ATP.
All three classes of molecules can enter the Krebs cycle through some intermediate;
therefore all three can be used for the synthesis of ATP.
Glucose can be broken down into products that can be used in the synthesis of fat or some amino acids,
by way of common intermediates such as pyruvate, oxaloacetate, and acetyl coenzyme A.
Similarly, the breakdown products of some amino acids can be used to synthesise glucose and fat.
Fatty acids cannot be used in the synthesis of glucose because of the irreversibility of the reaction,
converting pyruvate to acetyl coenzyme A,
but the glycerol portion of triglycerides can be used in the synthesis of glucose.
Fatty acids can be used to synthesise portions of the keto acids to form some amino acids.
Metabolism therefore, is a highly integrated process in which all classes of nutrient macromolecules,
can be used to provide energy, and in which each class of molecule can be used to synthesise,
most but not all members of other classes.
Review.
Catabolism of carbohydrates.
- A maximum of 38 molecules of ATP can form from catabolism of one molecule of glucose:
upto 34 from oxidative phosphorylation, 2 from glycolysis, 2 from the Krebs cycle.
Carbohydrates.
- Stored as glycogen in liver and skeleton muscles.
- Glycogenolysis : enzymatic process in which glucose is derived from glycogen.
- Gluconeogenesis : enzymatic process in which glucose is synthesised from breakdown products,
of some amino acids, lactate and glycerol.
- Fatty acids cannot be used to synthesise new glucose.
Triglycerides.
- Stored in adipose tissue ; provides about 80% of stored energy in the body.
Fatty acid catabolism and synthesis.
- Broken down in mitochondrial matrix by beta oxidation,
to form acetyl coenzyme A and H+ generated there, plus those generated during beta oxidation,
enter the oxidative phosphorylation pathway to form ATP.
- The amount of ATP formed by the catabolism of 1 gram of fat,
is about 2 1/2 times greater than the amount formed from 1 gram of carbohydrate.
- Synthesis from acetyl coenzyme A by cytosolic enzymes ;
Fatty acids linked to glycerol 3-phosphate to form triglycerides.
Protein catabolism.
- Broken down to free amino acids by proteases.
- Keto acids : formed by removal of amino groups from amino acids;
can be catabolised via the Krebs cycle to provide energy in synthesis of glucose and fatty acids.
- Amino groups removed by oxidative deamination, which gives rise to ammonia ;
or transamination, in which the amino group is transferred to a keto acid to form a new amino acid.
- Ammonia : used to form urea by enzymes in liver ; excreted in the urine.
Essential nutrients.
About 50 substances required for normal or optimal body function cannot be synthesised by the body,
or synthesised in amounts inadequate to keep pace with the rates,
at which they are broken down or excreted.
Such substances are known as essential nutrients.
Because they are all removed from the body at some finite rate,
they must be continuously supplied in the foods we eat.
The term essential nutrient is reserved for substances that fulfil 2 criteria :
1. They must be essential for health.
2. They must not be synthesised in the body in adequate amounts.
3. Therefore, glucose, though essential for normal metabolism,
is not an essential nutrient because the body normally can synthesise all it requires,
from amino acids, for example.
Furthermore, the quantity of an essential nutrient that must be present in the diet,
to maintain health is not a criteria for determining whether the substance is essential.
Approximately, 1500 grams of water, 2 grams of the amino acid methionine,
and only about 1 milligram of vitamin thiamine are required per day.
Water is an essential nutrient because the body loses far more water in the urine and from the skin,
and respiratory tract, then it can synthesise.
Water forms as an end product of oxidative phosphorylation,
as well as from several other metabolic reactions.
Therefore, to maintain water balance, water intake is essential.
The mineral elements are examples of substances the body cannot synthesise or breakdown,
but that the body continuously loses in the urine, feces, and various secretions.
The major minerals must be supplied in fairly large amounts,
whereas only small quantities of the trace elements are required.
9 of the 20 amino acids are essential.
2 fatty acids, linoleic and linolenic acid, which contain a number of double bonds,
and serve important functions in chemical messenger systems, are also essential nutrients.
3 additional essential nutrients inositol, choline and carnitine, do not fall into any carbon category,
other than being essential nutrients.
Finally, the class of essential nutrients known as vitamins deserves special attention.
Vitamins.
Vitamins are a group of 14 organic essential nutrients required in very small amounts in the diet.
The exact chemical structures of the first vitamins to be discovered were unknown,
and they were simply identified by letters of an alphabet.
Vitamin B turned out to be composed of 8 substances now known as vitamin B complex.
Plants and bacteria have the enzymes necessary for vitamin synthesis,
and we get our vitamins from eating either plants or meat from animals that eat plants.
The vitamins as a class have no particular chemical structure in common,
but they can be divided into the water soluble vitamins and the fat soluble vitamins.
The water soluble vitamins form portions of coenzymes such as NAD+, FAD, and coenzyme A.
The fat soluble vitamins (A, D, E and K) in general do not function as coenzymes.
For example, vitamin A (retinol) is used to form the light sensitive pigment in the eye,
and lack of this vitamin leads to night blindness.
The catabolism of vitamins does not provide chemical energy,
although some vitamins participate as coenzymes in chemical reactions,
that release energy from other molecules.
Increasing the amount of vitamin in the diet beyond a certain minimum,
does not necessarily increase the activity of those enzymes for which the vitamin functions as a coenzyme.
Only very small quantities of coenzymes participate in the chemical reactions that require them,
and increasing the concentration above this level does not increase the reaction rate.
The fate of large quantities of ingested vitamins varies depending on whether,
the vitamin is water soluble or fat soluble.
As the amount of water soluble vitamins in the diet is increased, so is the amount excreted in the urine.
Therefore the accumulation of these vitamins in the body is limited.
On the other hand fat soluble vitamins can accumulate in the body,
because they are poorly excreted by the kidneys,
and because they dissolve in the fat stores in adipose tissue.
The intake of very large quantities of fat soluble vitamins can produce toxic effects.
Review.
Essential nutrients:
- Necessary for health but cannot be synthesised in adequate amounts by the body,
and must therefore be provided in the diet.
- Includes water, minerals, certain amino acids and fatty acids, vitamins.
Water soluble vitamins:
- B vitamins and vitamin C are excreted in urine.
Fat soluble vitamins:
- Vitamins A, D, E and K.
- Ingestion of high amounts leads to accumulation in adipose tissue and may produce toxic effects.