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Term Paper on Amino Acids
Term Paper Contents:
- Term Paper on the Introduction to Amino Acids
- Term Paper on the Properties Conveyed by Side Chains
- Term Paper on the Amino Acids as Acids and Bases
- Term Paper on the Stereoisomerism of the Amino Acids
- Term Paper on the Classification of Amino Acids
Term Paper # 1. Introduction to Amino Acids:
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In chemical terms, a protein is a polymer of α-amino acids, that is, 2-amino carboxylic acids. Before we look at the way the amino acids are joined to form proteins, let us examine the nature of these building blocks as they occur in free form. This is not an academic exercise because tissues contain substantial amounts of each amino acid in solution, sometimes as much as several millimoles per kilogram.
This pool of free amino acids is the source of material for constructing proteins, but it is also actively metabolized to many other products, and derangement of amino acid turnover frequently has severe consequences. Several amino acids have another important function-they are used as chemical messengers to transmit impulses between nerves.
Proteins are constructed from 20 different amino acids, which have this general structure:
The molecule is shown in two ways, the first indicating the position of every bond, and the second using a common kind of shorthand notation in which substituent hydrogen atoms are lumped together without indicating bonds, and individual C = O bonds also are not drawn.
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We see that amino acids draw their properties from a hydrogen atom and three substituent groups on C – 2, the α-carbon atom. It is the nature of the R group that gives character to an individual amino acid, and we shall see that these groups, usually called the side chains, are all-important in determining the properties of proteins.
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2. Properties Conveyed by Side Chains:
The amino acids are commonly classified according to the character of their side chains.
Let us survey the nature and function of these side chains and consider them as we encounter their specific effects. The chemical functions in the structures can be recognized without the necessity of rote memorization. First we have glycine, which has no side chain, and which therefore occupies the least space of all of the amino acids. This is an important property in itself.
1. Hydrophobic Bulk:
Many of the amino acids are built to take up space without interacting with water. They are especially useful in shaping the interior of protein molecules.
Side chains that serve in this way include alkyl hydrocarbon groups –
aromatic rings –
A heterocyclic ring, in which the side chain is also attached to the ammonium group on C-2 –
and a thioether –
2. II-Bond Interaction:
When aromatic rings are stacked side by side, their-electrons of the rings interact to form weak bonds.
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Some amino acids have aromatic rings that bond in this way with each other or with other flat resonant structures –
(The dashed lines are intended to convey the existence of interaction between the rings.)
3. Hydrogen Bonding:
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The hydrogen bond is one in which a proton is partially shared between two atoms containing unpaired electrons, such as O, N or S –
The hydrogen bond is one of the most important in forming the structure of proteins, partially because many of the constituent amino acids have groups in their side chains containing such atoms, and all of these may form hydrogen bonds. Groups containing N and O make the side chains more polar, with a greater tendency to interact with water, but this tendency is counteracted by participation in hydrogen bonding.
For example, burial of the alcoholic hydroxyl groups of serine and threonine and the phenolic hydroxyl group of tyrosine in the interior of proteins is often facilitated by hydrogen bonding, sometimes to an adjacent group –
Strongly polar groups are frequently near the surface of protein molecules because of their ready association with water, but they also can form hydrogen bonds that sometimes enable them to be buried.
They include, along with frankly ionic carboxylate and ammonium groups considered below, the carboxamide groups of asparagine and glutamine.
4. Binding of Metallic Cations:
Atoms with unshared electrons are sometimes used to bind metals, or groups containing metals.
For example, the imidazole ring of a histidyl side chain binds the iron atom in hemoglobin, and the thiol ether group of methionine has a similar purpose in other proteins –
Carboxylate and amino groups also readily bond metallic ions, hence synthetic amino acids and related compounds were developed for this purpose.
One that is widely used both as a reagent and as a drug is ethylenedinitrilotetraacetate or EDTA (also known as ethylenediam-inetetraacetate) –
EDTA has a high affinity for metal cations with two or more negative charges. It is used to treat lead poisoning because the lead chelate is soluble and can be excreted. It is administered as the disodium salt of the calcium chelate.
This is because it must be given in excess in order to compete with the many reactive groups in the body that also have a high affinity for lead; if the tetra-sodium salt were given, the excess would remove calcium from the body.
EDTA has a higher affinity for lead than it does for calcium, so lead will displace calcium –
5. Ionized Side Chains:
Some amino acids have ionized groups in their side chains that cause strong affinity for water where they occur in proteins.
These include amino acids with carboxylate groups, and amino acids with positively charged groups containing nitrogen atoms –
The positively and negatively charged side chains can form bonds through electrostatic interaction, and they can also form hydrogen bonds and bind metallic cations.
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3. Amino Acids as Acids and Bases:
Amino acids can both donate and accept protons; they are therefore said to be amphoteric.
Every amino acid in neutral solution can behave as an acid because it contains at least one charged ammonium group from which a proton can dissociate –
Similarly, it behaves as a base because it contains at least one charged carboxylate group that can accept a proton –
Consider the simplest amino acid, glycine.
It can equilibrate with H+ in two ways –
The form shown in the middle is a zwitterion, meaning hermaphrodite ion, because it has equal numbers of positive ammonium groups and negative carboxylate groups, although its net charge is zero. It behaves as a base because the carboxylate groups will combine with increasing concentrations of H+ to form uncharged COOH groups.
The remaining ammonium group then gives the molecule a net positive charge (cationic form). On the other hand, the zwitterion can behave as an acid because the ammonium group will lose H+ when the concentration of H+ is lowered, leaving an uncharged amino group. The molecule then has a net negative charge from the remaining carboxylate group (anionic form).
What is the physiological form of glycine? We see that glycine exists mostly as a zwitterion over a broad range centered near 10-6 M H+ (pH 6). In general, amino acids with one ammonium group and one carboxylate group exist mainly as the zwitterion in physiological fluids.
For example, here is the distribution of the various forms of glycine at pH 7.4 ([H+] = 10-7.1 M), which is the normal pH of blood plasma:
Other amino acids with one ammonium group and one carboxylate group behave as acids and bases in much the same way as does glycine with the zwitterion being the physiological form of each.
Why the molecules are called amino acids? Well, the original investigators thought that the uncharged form predominated. This form has an authentic amino group and a carboxyl group, which makes it both an amine and a carboxylic acid. We have known for many decades that it is almost non-existent, but many still draw amino acids that way.
Acidic and Basic Side Chains:
The carboxylate and substituted ammonium groups on the side chains of some amino acids also behave as acids and bases. This is still true when the amino acids are combined to form proteins, so these are the groups mainly responsible for giving amphoteric properties to proteins. The general principles can be grasped by examining the behaviour of amino acids containing such side chains.
Carboxylate Side Chains:
Consider Aspartic Acid:
Here we have three distinct equilibria. The ammonium group doesn’t behave much differently than the ammonium group of glycine, but the side chain carboxylic group is a weaker acid than the group on glycine, and the 1-carboxylic group is a stronger acid. The shift in the proportion of the ionic forms with changes in H+ concentration is shown in Figure. The zwitterions of aspartate and glutamate occur in acidic solution, whereas physiological fluids contain the fully ionized forms with one net negative charge. Monosodium glutamate, which is used as a food seasoning, gives a nearly neutral solution.
Cationic Side Chains:
Three amino acids have side chains that may be positively charged under physiological conditions. Lysine has an ammonium group at the end of a hydrocarbon tail. This group is an even weaker acid than the ammonium group on C-2, which means that it will retain its positive charge at even lower H+ concentrations (higher pH values).
The result is that both of the ammonium groups of lysine, in addition to the carboxylate group, are charged in physiological fluids, and the physiological form is therefore a cation with one net positive charge.
The guanidinium group on the side chain of arginine is an even weaker acid. Put another way, free guanidine groups are very strong bases, almost as strong as hydroxide ion itself, and they bind protons avidly.
Therefore, the side chain of arginine retains its positive charge in all but strongly alkaline solutions, and the physiological form also is the cation with one net positive charge –
Histidine is Different:
The imidazole group in its side chain is approximately half- ionized at pH 6.1 (H+ = 10-6.1 M) — sometimes as high as pH 7 when the amino acid is used to form proteins.
This means that the physiological form of histidine is a mixture of the zwitterion and the cationic forms –
The facility with which the side chain of histidine can switch from being an acid to being a base is an important feature for many biological functions, including the catalytic properties of enzymes.
Isoelectric Point:
The charges on carboxylate ions can be repressed by increasing the concentration of H+, while the ammonium groups (and similar cationic groups) can be made to lose their charge by decreasing the concentration of H+. It follows that for each compound carrying both carboxylate and ammonium groups there is some value of the hydrogen ion concentration at which the number of negatively charged carboxylate groups will exactly equal the number of positively charged groups.
This is true no matter how many of the respective groups there may be on a molecule. The H+ concentration at which this occurs, usually expressed as a pH value, is known as the isoelectric point for the compound. It is the pH at which the molecule will fail to migrate in an electric field because it has no net charge.
Some of the molecules may bear a net negative charge at a given moment, but they will be counterbalanced by an equal number of molecules bearing a net positive charge; the number of molecules that are zwitterions is greatest at the isoelectric point.
As the pH, of a solution is raised above the isoelectric point of an amphoteric compound (decreasing acidity), an increasing number of molecules will bear a net negative charge, owing to the loss of H+ from the counterbalancing cationic groups. The compound will then migrate to the positive pole in an electric field.
When the pH is lowered below the isoelectric point (increasing acidity), an increasing number will bear a net positive charge, owing to the gain of H+ by previously charged carboxylate groups to form the uncharged carboxylic acids. The compound will then migrate to the negative pole in an electric field.
Calculation of the Isoelectric Point:
The ionizations of simple mono-amino, monocarboxylic acids are described by two acidic dissociation constants –
The isoelectric point occurs when [R – NH2] = [R – COOH], and a little algebraic manipulation shows that this happens when [H+] = √K1K2. Put in logarithmic form,
isoelectric pH = pI = ½ (pK1 + pK2)
in which pK1 and pK2 are the negative logarithms of the respective dissociation constants.
Consider leucine as an example:
K1 = 10-2.36; K2 = 10-9.60
pI = ½ (2.36 + 9.60) = 5.98
Most of the mono-amino, monocarboxylic acids have isoelectric points near pH 6.
What is the isoelectric point of a dicarboxylic, mono-amino acid such as aspartate? It is a pH halfway between the pK values for the two carboxylic acid groups – pI = ½ (1.99 + 3.90) = 2.95. At this acidic pH, sufficient protons add to the two carboxylate groups to leave only one remaining negative charge, while the ammonium group (pK = 9.90) is almost totally charged.
Similarly, the isoelectric point of a monocarboxylic, di-amino acid such as lysine is a pH halfway between the pK values for the two ammonium groups – pI = ½ (9.18 + 10.79) = 9.99. At this alkaline pH, only one H+ remains attached to the two amino groups, while the lone carboxylate group (pK = 2.16) is totally ionized for all practical purposes.
Ionization and Solubility:
The isoelectric points provide useful information for reasoning about the behaviour of amino acids in solution because of the relationship they have to the various ionic forms. For example, the presences of charged groups on amino acids and proteins have important effects on their solubility.
Amino acids and proteins are least soluble at the isoelectric point, other things being equal. This is so because the zwitterion has no net charge, and it can therefore crystallize as such.
The anionic or cationic forms can crystallize only as salts, such as sodium glycinate or glycine hydrochloride –
Since these salts can freely dissociate in water, they are much more soluble.
Does this mean that amino acids with isoelectric points near the pH of physiological fluid are likely to crystallize in the tissues? No, it does not because the zwitterions, while having no net charge, do have an off-axis distribution of positive and negative charges that create strong dipoles in the molecule, thereby making nearly all quite soluble in water, even though they are less soluble than the ionic forms. This is generally true even when abnormally high concentrations of amino acids result from genetic defects (aminoacidopathies).
There is one conspicuous exception. Cystine is an amino acid that contains two ammonium groups and two carboxylate groups because it is formed by linking two molecules of another amino acid, cysteine, through side chain sulfur atoms.
The crystal lattice of this molecule is so stable that the zwitterion is only soluble to the extent of 160 mg per liter of water at 37°C.
This low solubility causes trouble in people born with a genetic defect known as cystinuria that causes them to excrete high quantities of the amino acid in the urine. The H+ concentration of urine frequently ranges near the isoelectric point for cystine (10-5 M, pH 5.0), at which the amino acid is least soluble.
The presence of other compounds in the urine increases the solubility of cystine to approximately 300 mg per liter through “salting in” and the formation of complexes, but cystinuric patients frequently excrete even more than this, with the excess crystallizing into stones in the kidneys, ureters, and bladder. (The problem is not uncommon; over 1 per cent of the stones found in urinary tracts contain cystine as a major component.)
Could something be done to increase the solubility of cystine in the urine? One way of doing this would be to shift the pH from the isoelectric point. We see that a shift of over 2 pH units (100- fold change in [H+]) would be required in order to convert 10 per cent of the zwitterion to the anionic form.
However, the solubility increases rapidly beyond that point, and it is indeed possible to keep substantially greater amounts of cystine in solution by prescribing repeated doses of sodium bicarbonate to the patient so as to raise his urinary pH over 7.0. Unfortunately, the promise of this therapy proved somewhat illusory; the diminished acidity also increases the concentration of fully ionized phosphate in the urine, causing an increased precipitation of calcium phosphate in the stones. The result is the replacement of one rocky insult to the urinary treat by another.
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4. Stereoisomerism of the Amino Acids:
Let us briefly review what organic chemistry tells us about stereoisomers as it applies to the amino acids. All of the amino acids that are introduced into peptide chains by protein synthesis have one carbon (C-2) that is bonded to four different groups, except glycine, which has two H atoms.
There are two possible arrangements of groups around such an asymmetric center:
Amino acids having one of the arrangements are said to have the L-configuration; those with the other have the D-configuration. The two configurations are mirror images of each other and like all mirror images of asymmetric objects cannot be superimposed no matter how they are turned. They are said to be enantiomorphic isomers, or enantiomers.
All of the asymmetric amino acids occurring in proteins belong to the L configurational family. This is true even though the D and L isomers have many identical chemical and physical properties. The important difference between them is that they cannot approach a fixed arrangement of groups, such as occur in another asymmetric compound, in the same way, and most biochemical reactions hinge upon mating arrangements between asymmetric groups.
In the case of the amino acids, the distinction is so critical that many microorganisms deliberately use D-amino acids to create peptides that are highly toxic to other organisms; that is, they are antibiotics. The animal kidney has the ability to destroy D-amino acids, apparently to eliminate any possibility of forming toxic peptides.
Diastereoisomers:
Some amino acids have more than one asymmetric carbon atom.
Consider L-threonine, which has four possible stereoisomers:
Each of the four is a different compound, and only one, L-threonine, occurs naturally in proteins. There are two mirror-image pairs represented, and the two pairs are given different names. This is so because D- and L-threonine have similar behavior with symmetrical chemical reagents, and D- and L-allothreonine have similar behaviour, but L-threonine and L-allothreonine behave differently and have different melting points, solubility’s, and so on. They are said to be diastereoisomers.
It is common to designate a stereoisomer in structural formulas by a convention in which all vertical bonds are directed behind the plane of the paper and all horizontal bonds are directed in front of the plane of the paper.
There are 12 ways in. which a molecule of L-alanine, for example, can be written with the vertical bonds behind the plane of the paper.
Some of them are shown in the following:
A useful rule of thumb is that interchanging any two substituents on each asymmetric carbon in a conventional structural formula gives a representation of the other stereoisomer; making any two such interchanges gives another representation of the same stereoisomer.
Designating Rotation:
We designate all of the amino acids having the same arrangement of groups around C-2 found in L-alanine as L-amino acids regardless of the arrangement about other asymmetric centers. Some L-amino acids cause a rotation of a plane polarized light to the left, others to the right.
The direction of rotation is shown when desired by lower case italic letters (d) or (1) in parentheses to designate dextro- or levorotatory, respectively. (It can also be shown by (+) for dextro- and (-) for levo-.) The older literature is confusing in this respect because there was a time of transition when the lower case letters were used for configurational family as well as for actual rotation.
R and S Nomenclature:
Because of the difficulty sometimes created in designating configurational family with many types of compounds, a new nomenclature has been invented. Briefly, each of the four constituent groups about an asymmetric carbon is arranged in order of increasing atomic number of the nearest constituent atom or in order of increasing valence electron density. (N ranks higher than C, and O higher than N; ethylene carbons rank higher than saturated carbons, a —CH2—COO– group ranks higher than a — CH2—CH3 group, and so on.) One looks at the asymmetric center in such a way as to peer directly down on the substituent of lowest rank order, which is frequently -H with the amino acids.
When this is done, the remaining three substituents will be arranged- as spokes on a wheel, and one goes around the wheel from the lowest rank order to the highest. If this is a clockwise direction, the configuration is rectus or (R); if it is counterclockwise; the configuration is sinistrus or (S).
The process is repeated for each asymmetric center. Designating the isomers does take some practice in visualization of the structures, but the nomenclature has the advantage of creating an unambiguous designation of the absolute configuration, no matter how many asymmetric centers there are. Under this system, L-threonine is (2S:3R)-threonine, or more systematically, (2S:3R)-2-amino-3-hydroxybutyrate.
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5. Classification of Amino Acids:
Amino acids can be classified in two ways – based on structure and polarity.
1. Based on Structure:
Based on structure, amino acids are grouped into three classes as:
A. Aliphatic Amino Acids:
These are straight or open chain amino acids which are further subdivided into four groups as:
i. Monoaminomonocarboxylic (Neutral) Amino Acids:
These consist of one amino and one carboxyl groups and hence are neutral to litmus, e.g. glycine, alanine, valine, leucine, isoleucine, serine and threonine.
ii. Monoaminodicarboxylic (Acidic) Amino Acids:
These consist of one amino and two carboxyl groups and hence are acidic to litmus, e.g. aspartic acid and glutamic acid.
iii. Monocarboxylicdiamino (Basic) Amino Acids:
These consist of one carboxyl and two amino groups and hence are basic to litmus, e.g. lysine, arginine and histidine.
iv. Sulphur-Containing Amino Acids:
These consist of one or more sulphur atoms, e.g. cysteine, cystine and methionine.
B. Aromatic Amino Acids:
These contain an aromatic ring in the molecule, e.g. phenylalanine and tyrosine.
C. Heterocyclic Amino Acids:
These contain an heterocyclic nucleus in the molecule, e.g. histidine, tryptophan, proline and hydroxyproline.
2. Based on Polarity:
The most meaningful way of classification of amino acids is based on polarity and accordingly they are classified into four groups as those with:
i. Nonpolar or Hydrophobic R Groups:
These amino acids are relatively less soluble in water than those with polar R groups, e.g. alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan and proline. The least hydrophobic member of this class is alanine which is near the border line between the nonpolar amino acids and those with uncharged polar R groups.
ii. Uncharged Polar R Groups:
These are relatively more soluble in water than the first group because of the presence of polar R groups (indicated within brackets), e.g. glycine (H+), serine (OH–), threonine (OH–), tyrosine (phenolic hydroxyl) and cysteine (-SH or thiol group). Glycine is the border line member of this class and is sometimes even grouped in the first category.
The remaining amino acids are weakly hydrophilic as their R groups do not ionize at physiological pH values and hence remain unchanged. Cysteine and tyrosine have the most polar substituents of this class of amino acids. Cysteine often occurs in proteins in its oxidized form, cystine.
iii. Positively Charged R Groups:
Amine acids such as lysine, histidine and arginine (basic amino acids) having positively charged R group at physiological pH belong to this category and are strongly hydrophilic. The positive charge arises because these amino acids possess nitrogen-containing R groups (Î – NH2 group in lysine, guanidino group in arginine and imidazole group in histidine) that accept protons in aqueous solution at neutral or acidic pH.
iv. Negatively Charged R Groups:
Amino acids namely, aspartic acid and glutamic acid (acidic amino acids) each with a second carboxyl group in addition to a- carboxyl group give up a proton in aqueous solution at neutral or basic pH and hence possess an extra negative charge at physiological pH. Because of this, they are strongly electrophilic.