amino acids: chemistry and properties · l-amino acids that are found. d-amino acids occur...
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Amino acids: chemistry andproperties
A. Amino acids: functions �
The amino acids (2-aminocarboxylic acids)fulfill various functions in the organism.Above all, they serve as the components ofpeptides and proteins. Only the 20 proteino-genic amino acids (see p. 60) are included inthe genetic code and therefore regularlyfound in proteins. Some of these amino acidsundergo further (post-translational) changefollowing their incorporation into proteins(see p. 62). Amino acids or their derivativesare also form components of lipids—e. g., ser-ine in phospholipids and glycine in bile salts.Several amino acids function asneurotransmitters themselves (see p. 352),while others are precursors of neurotransmit-ters, mediators, or hormones (see p. 380).Amino acids are important (and sometimesessential) components of food (see p. 360).Specific amino acids form precursors for othermetabolites—e. g., for glucose in gluconeogen-esis, for purine and pyrimidine bases, forheme, and for other molecules. Several non-proteinogenic amino acids function as inter-mediates in the synthesis and breakdown ofproteinogenic amino acids (see p. 412) and inthe urea cycle (see p.182).
B. Optical activity �
The natural amino acids are mainly α-aminoacids, in contrast to β-amino acids such as β-alanine and taurine. Most α-amino acids havefour different substituents at C-2 (Cα). The αatom therefore represents a chiral center—i. e.,there are two different enantiomers (L- andD-amino acids; see p. 8). Among the proteino-genic amino acids, only glycine is not chiral (R= H). In nature, it is almost exclusivelyL-amino acids that are found. D-Amino acidsoccur in bacteria—e. g., in murein (seep. 40)—and in peptide antibiotics. In animalmetabolism, D-Amino acids would disturbthe enzymatic reactions of L-amino acidsand they are therefore broken down in theliver by the enzyme D-amino acid oxidase.
The Fischer projection (center) is used topresent the formulas for chiral centers in bio-molecules. It is derived from their three-di-
mensional structure as follows: firstly, thetetrahedron is rotated in such a way that themost oxidized group (the carboxylate group)is at the top. Rotation is then continued untilthe line connecting line COO– and R (red) islevel with the page. In L-amino acids, theNH3
+ group is then on the left, while in D-amino acids it is on the right.
C. Dissociation curve of histidine �
All amino acids have at least two ionizablegroups, and their net charge therefore de-pends on the pH value. The COOH groups atthe α-C atom have pKa values of between 1.8and 2.8 and are therefore more acidic thansimple monocarboxylic acids. The basicity ofthe α-amino function also varies, with pKa
values of between 8.8 and 10.6, dependingon the amino acid. Acidic and basic aminoacids have additional ionizable groups in theirside chain. The pKa values of these side chainsare listed on p. 60. The electrical charges ofpeptides and proteins are mainly determinedby groups in the side chains, as most α-car-boxyl and α-amino functions are linked topeptide bonds (see p. 66).
Histidine can be used here as an example ofthe pH-dependence of the net charge of anamino acid. In addition to the carboxyl groupand the amino group at the α-C atom with pKa
values of 1.8 and 9.2, respectively, histidinealso has an imidazole residue in its side chainwith a pKa value of 6.0. As the pH increases,the net charge (the sum of the positive andnegative charges) therefore changes from +2to –1. At pH 7.6, the net charge is zero, eventhough the molecule contains two almostcompletely ionized groups in these condi-tions. This pH value is called the isoelectricpoint.
At its isoelectric point, histidine is said tobe zwitterionic, as it has both anionic andcationic properties. Most other amino acidsare also zwitterionic at neutral pH. Peptidesand proteins also have isoelectric points,which can vary widely depending on thecomposition of the amino acids.
58 Biomolecules
R
H
COO
R
H
COO
H3N H3NC C
R
C HH3N
COO
R
CH
COO
H3N
2
6
pK39.2
pK26.0
pK11.8
8
10
12
pH
4
0-1 +1 +2
COO
CH3N
CH2
H
CHN
HC N
CH
COO
CH2N
CH2
H
CHN
HC N
CH
COOH
CH3N
CH2
H
CHN
HC NH
CH
COO
CH3N
CH2
H
CHN
HC NH
CH
A. Amino acids: functions
B. Optical activity
(Isoelectric point)
C. Dissociation curve of histidine
L-Amino acid D-Amino acid (mirror image)Fischer projections
pH 11
pH 5pH 0.5
pH 7.6
Net charge
Components of:
PeptidesProteinsPhospholipids
Neurotransmitters:
GlutamateAspartateGlycine
L-Amino acid
Precursors of:
Keto acidsBiogenic aminesGlucoseNucleotidesHeme, creatine
Transport molecule for:
NH2 groups
R
59Amino Acids
Proteinogenic amino acids
A. The proteinogenic amino acids �
The amino acids that are included in the ge-netic code (see p. 248) are described as “pro-teinogenic.” With a few exceptions (see p. 58),only these amino acids can be incorporatedinto proteins through translation. Only theside chains of the 20 proteinogenic aminoacids are shown here. Their classification isbased on the chemical structure of the sidechains, on the one hand, and on their polarityon the other (see p. 6). The literature includesseveral slightly different systems for classify-ing amino acids, and details may differ fromthose in the system used here.
For each amino acid, the illustration names:• Membership of structural classes I–VII (see
below; e. g., III and VI for histidine)• Name and abbreviation, formed from the
first three letters of the name (e. g., histi-dine, His)
• The one-letter symbol introduced to savespace in the electronic processing of se-quence data (H for histidine)
• A quantitative value for the polarity of theside chain (bottom left; 10.3 for histidine).The more positive this value is, the morepolar the amino acid is.
In addition, the polarity of the side chains isindicated by color. It increases from yellow,through light and dark green, to bluish green.For ionizing side chains, the correspondingpKa values are also given (red numbers).
The aliphatic amino acids (class I) includeglycine, alanine, valine, leucine, and isoleucine.These amino acids do not contain heteroa-toms (N, O, or S) in their side chains and donot contain a ring system. Their side chainsare markedly apolar. Together with threonine(see below), valine, leucine, and isoleucineform the group of branched-chain aminoacids. The sulfurcontaining amino acids cys-teine and methionine (class II), are also apolar.However, in the case of cysteine, this onlyapplies to the undissociated state. Due to itsability to form disulfide bonds, cysteine playsan important role in the stabilization of pro-teins (see p. 72). Two cysteine residues linkedby a disulfide bridge are referred to as cystine(not shown).
The aromatic amino acids (class III) containresonancestabilized rings. In this group, onlyphenylalanine has strongly apolar properties.Tyrosine and tryptophan are moderately polar,and histidine is even strongly polar. The imi-dazole ring of histidine is already protonatedat weakly acidic pH values. Histidine, which isonly aromatic in protonated form (see p. 58),can therefore also be classified as a basicamino acid. Tyrosine and tryptophan showstrong light absorption at wavelengths of250–300 nm.
The neutral amino acids (class IV) havehydroxyl groups (serine, threonine) or amidegroups (asparagine, glutamine). Despite theirnonionic nature, the amide groups of aspara-gine and glutamine are markedly polar.
The carboxyl groups in the side chains ofthe acidic amino acids aspartic acid and glu-tamic acid (class V) are almost completelyionized at physiological pH values. The sidechains of the basic amino acids lysine andarginine are also fully ionized—i. e., positivelycharged—at neutral pH. Arginine, with itspositively charge guanidinium group, is par-ticularly strongly basic, and therefore ex-tremely polar.
Proline (VII) is a special case. Together withthe α-C atom and the α-NH2 group, its sidechain forms a fivemembered ring. Its nitrogenatom is only weakly basic and is not proto-nated at physiological pH. Due to its ringstructure, proline causes bending of the pep-tide chain in proteins (this is important incollagen, for example; see p. 70).
Several proteinogenic amino acids cannotbe synthesized by the human organism, andtherefore have to be supplied from the diet.These essential amino acids (see p. 360) aremarked with a star in the illustration. Histi-dine and possibly also arginine are essentialfor infants and small children.
60 Biomolecules
–2.4 –1.9 –2.0 –2.3 –2.2 –1.2 –1.5
8.3
+0.8 +6.1 +5.9 +6.0 +5.1 +4.9
10.1
6.04.3
4.0
12.510.8
+9.7 +9.4 +11.0 +10.2 +10.3 +15.0 +20.0
H CH3 CH
CH3
H3C CH2
CH
CH3
H3C
C
CH2
H3C H
CH3
CH2
SH
CH2
CH2
S
CH3
C
OH
H3C HCH2
OHCHHN
H2C CH2
CH2
COO
NH
CH2CH2
OH
CH2
CH2
CONH2
CH2
CH2
CONH2
CH2
COO
CH2
HN
HC N
CH
CH2
CH2
CH2
NH
CH2N NH2
CH2
CH2
CH2
CH2
NH3
CH2
CH2
COO
(Gly, G) (Ala, A) (Val, V) (Leu, L) (Ile, I) (Cys, C) (Met, M)Glycine Cysteine
Aliphatic
Alanine Valine Leucine Isoleucine Methionine
Sulfur-containing
pKa value
A. The proteinogenic amino acids
Chiral center
(Phe, F) (Tyr, Y) (Trp, W) (Pro, P) (Ser, S) (Thr, T)Proline
Aromatic Cyclic
Phenylalanine Tyrosine Tryptophan Serine Threonine
Neutral
(Asn,N) (Gln, Q) (Asp, D) (Glu, E) (His, H) (Lys,K) (Arg, R)
Aspartic acid
Acidic
Asparagine Glutamine Glutamic acid Histidine Lysine Arginine
Neutral Basic
Polarity
Essential amino acids
Indole ring Pyrrolidine ring
Imidazole ring
61Amino Acids
Non-proteinogenic amino acids
In addition to the 20 proteinogenic aminoacids (see p. 60), there are also many morecompounds of the same type in nature. Thesearise during metabolic reactions (A) or as aresult of enzymatic modifications of aminoacid residues in peptides or proteins (B). The“biogenic amines” (C) are synthesized from α-amino acids by decarboxylation.
A. Rare amino acids �
Only a few important representatives of thenon-proteinogenic amino acids are men-tioned here. The basic amino acid ornithineis an analogue of lysine with a shortened sidechain. Transfer of a carbamoyl residue to or-nithine yields citrulline. Both of these aminoacids are intermediates in the urea cycle (seep.182). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in thebiosynthesis of catecholamines (see p. 352)and of melanin. It is in clinical use in thetreatment of Parkinson’s disease. Selenocys-teine, a cysteine analogue, occurs as a compo-nent of a few proteins—e. g., in the enzymeglutathione peroxidase (see p. 284).
B. Post-translational protein modification �
Subsequent alteration of amino acid residuesin finished peptides and proteins is referredto as post-translational modification. These re-actions usually only involve polar amino acidresidues, and they serve various purposes.
The free α-amino group at the N-terminusis blocked in many proteins by an acetyl res-idue or a longer acyl residue (acylation). N-terminal glutamate can cyclize into a pyroglu-tamate residue, while the C-terminal carbox-ylate group can be present in an amidatedform (see TSH, p. 380). The side chains of ser-ine and asparagine residues are often linkedto oligosaccharides (glycosylation, see p. 230).Phosphorylation of proteins mainly affectsserine and tyrosine residues. These reactionshave mainly regulatory functions (see p.114).Aspartate and histidine residues of enzymesare sometimes phosphorylated, too. A specialmodification of glutamate residues, -carbox-ylation, is found in coagulation factors. It isessential for blood coagulation (see p. 290).
The ε-amino group of lysine residues is sub-ject to a particularly large number of modifi-cations. Its acetylation (or deacetylation) is animportant mechanism for controlling geneticactivity (see p. 244). Many coenzymes andcofactors are covalently linked to lysine resi-dues. These include biotin (see p.108), lipoicacid (see p.106), and pyridoxal phosphate(see p.108), as well as retinal (see p. 358).Covalent modification with ubiquitin marksproteins for breakdown (see p.176). In colla-gen, lysine and proline residues are modifiedby hydroxylation to prepare for the formationof stable fibrils (see p. 70). Cysteine residuesform disulfide bonds with one another (seep. 72). Cysteine prenylation serves to anchorproteins in membranes (see p. 214). Covalentbonding of a cysteine residue with heme oc-curs in cytochrome c. Flavins are sometimescovalently bound to cysteine or histidine res-idues of enzymes. Among the modifications oftyrosine residues, conversion into iodinatedthyroxine (see p. 374) is particularly interest-ing.
C. Biogenic amines �
Several amino acids are broken down by de-carboxylation. This reaction gives rise to whatare known as biogenic amines, which havevarious functions. Some of them are compo-nents of biomolecules, such as ethanolaminein phospholipids (see p. 50). Cysteamine and
-alanine are components of coenzyme A (seep.12) and of pantetheine (see pp.108, 168).Other amines function as signaling substan-ces. An important neurotransmitter derivedfrom glutamate is γ-aminobutyrate (GABA,see p. 356). The transmitter dopamine is alsoa precursor for the catecholamines epineph-rine and norepinephrine (see p. 352). The bio-genic amine serotonin, a substance that hasmany effects, is synthesized from tryptophanvia the intermediate 5-hydroxytryptophan.
Monamines are inactivated into aldehydesby amine oxidase (monoamine oxidase,“MAO”) with deamination and simultaneousoxidation. MAO inhibitors therefore play animportant role in pharmacological interven-tions in neurotransmitter metabolism.
62 Biomolecules
HN N
COO
C
CH2
CH2
CH2
NH3
H3N H
COO
C
CH2
CH2
CH2
N
H3N H
C NH2
O
H
COO
C
CH2
H3N H
OH
OH
COO
C
CH2
H3N H
Se H
NH3COOCONH2OH
SH
OH
OOC
H3N
Neurotrans-mitter (GABA)
A. Rare amino acids
D: Pyroglutamyl-Acetyl-Formyl-Myristoyl-
B: Oligo-saccharide
(O-glyco-sylation)
B: Oligo-saccharide
(N-glyco-sylation)
D: Phospho-Methyl-γ-Carboxy-(Glu)
D: Acetyl-Methyl-γ-Hydroxy-
B: Pyridoxal-LiponatBiotinRetinalUbiquitin
Ser, Thr Asn, Gln Asp, Glu Lys
Tyr Phe His Cys
Pro
Ornithine Citrulline L-DopaSeleno-cysteine
D: derivative B: bonds with
Amine Function FunctionAmineAmino acidSerine Ethanol-
amineGlutamate
Cysteine Cysteamine Component ofcoenzyme A
Threonine Amino-propanol
Component ofvitamin B12
Aspartate β-Alanine Component ofcoenzyme A
γ-Amino-butyrate
Histidine Mediator, neuro-transmitter
Dopa Dopamine Neurotransmitter
5-Hydroxy-tryptophan
Serotonin Mediator, neuro-transmitter
Amino acid
D: DisulfidePrenyl-
B: HemeFlavin
D: Phospho-Methyl-
B: Flavin
D: 4-Hydroxy-(Tyrosine)
D: Phospho-Iodo-Sulfato-Adenyl-
D: Amido-(CONH2)
D: 3-Hydroxy-4-Hydroxy-
B. Post-translational protein modification
C. Biogenic amines
Glutamate
Histamine
63Amino Acids
Peptides and proteins: overview
A. Proteins �
When amino acids are linked together byacid–amide bonds, linear macromolecules(peptides) are produced. Those containingmore than ca. 100 amino acid residues aredescribed as proteins (polypeptides). Everyorganism contains thousands of different pro-teins, which have a variety of functions. At amagnification of ca. 1.5 million, the semi-schematic illustration shows the structuresof a few intra and extracellular proteins, giv-ing an impression of their variety. The func-tions of proteins can be classified as follows.
Establishment and maintenance of struc-ture. Structural proteins are responsible forthe shape and stability of cells and tissues. Asmall part of a collagen molecule is shown asan example (right; see p. 70). The completemolecule is 1.5 300 nm in size, and at themagnification used here it would be as long asthree pages of the book. Histones are alsostructural proteins. They organize the ar-rangement of DNA in chromatin. The basiccomponents of chromatin, the nucleosomes(top right; see p. 218) consist of an octamericcomplex of histones, around which the DNA iscoiled.
Transport. A wellknown transport proteinis hemoglobin in the erythrocytes (bottomleft). It is responsible for the transport of oxy-gen and carbon dioxide between the lungsand tissues (see p. 282). The blood plasmaalso contains many other proteins with trans-port functions. Prealbumin (transthyretin;middle), for example, transports the thyroidhormones thyroxin and triiodothyronine. Ionchannels and other integral membrane pro-teins (see p. 220) facilitate the transport ofions and metabolites across biological mem-branes.
Protection and defense. The immune sys-tem protects the body from pathogens andforeign substances. An important componentof this system is immunoglobulin G (bottomleft; see p. 300). The molecule shown here isbound to an erythrocyte by complex forma-tion with surface glycolipids (see p. 292).
Control and regulation. In biochemical sig-nal chains, proteins function as signaling sub-stances (hormones) and as hormone recep-tors. The complex between the growth
hormone somatotropin and its receptor isshown here as an example (middle). Here,the extracellular domains of two receptormolecules here bind one molecule of the hor-mone. This binding activates the cytoplasmicdomains of the complex, leading to furtherconduction of the signal to the interior ofthe cell (see p. 384). The small peptidehormone insulin is discussed in detail else-where (see pp. 76, 160). DNA-binding proteins(transcription factors; see p.118) are decisivelyinvolved in regulating the metabolism and indifferentiation processes. The structure andfunction of the catabolite activator protein(top left) and similar bacterial transcriptionfactors have been particularly well investi-gated.
Catalysis. Enzymes, with more than 2000known representatives, are the largest groupof proteins in terms of numbers (see p. 88).The smallest enzymes have molecular massesof 10–15 kDa. Intermediatesized enzymes,such as alcohol dehydrogenase (top left) arearound 100–200 kDa, and the largest—including glutamine synthetase with its 12monomers (top right)—can reach more than500 kDa.
Movement. The interaction between actinand myosin is responsible for muscle contrac-tion and cell movement (see p. 332). Myosin(right), with a length of over 150 nm, isamong the largest proteins there are. Actinfilaments (F-actin) arise due to the polymer-ization of relatively small protein subunits (G-actin). Along with other proteins, tropomyo-sin, which is associated with F-actin, controlscontraction.
Storage. Plants contain special storage pro-teins, which are also important for humannutrition (not shown). In animals, muscleproteins constitute a nutrient reserve thatcan be mobilized in emergencies.
64 Biomolecules
Hemoglobin
Immuno-globulin G
PrealbuminWater
Glucose
Cholesterol
Ion channel
Alcoholdehydrogenase
DNACatabolite activatorprotein
Glutaminesynthetase
Myosin
F-Actin
Nucleus
10 nm
Cyto-plasm
Nucleosome
Somatotropinreceptor(dimer)
Somatotropin
Insulin
Blood
Collagentriple helix
Tropo-myosin
A. Proteins
Erythrocyte
65Peptides and Proteins
Peptide bonds
A. Peptide bond �
The amino acid components of peptides andproteins are linked together by amide bonds(see p. 60) between α-carboxyl and α-aminogroups. This type of bonding is therefore alsoknown as peptide bonding. In the dipeptideshown here, the serine residue has a freeammonium group, while the carboxylategroup in alanine is free. Since the amino acidwith the free NH3
+ group is named first, thepeptide is known as seryl alanine, or in abbre-viated form Ser-Ala or SA.
B. Resonance �
Like all acid–amide bonds, the peptide bond isstabilized by resonance (see p. 4). In the con-ventional notation (top right) it is representedas a combination of a C=O double bond with aC–N single bond. However, a C=N double bondwith charges at O and N could also be written(middle). Both of these are only extreme casesof electron distribution, known as resonancestructures. In reality, the π electrons aredelocalized throughout all the atoms (bot-tom). As a mesomeric system, the peptidebond is planar. Rotation around the C–Nbond would only be possible at the expenseof large amounts of energy, and the bond istherefore not freely rotatable. Rotations areonly possible around the single bonds markedwith arrows. The state of these is expressedusing the angles φ and ψ (see D). The plane inwhich the atoms of the peptide bond lie ishighlighted in light blue here and on the fol-lowing pages.
C. Peptide nomenclature �
Peptide chains have a direction and thereforetwo different ends. The amino terminus (Nterminus) of a peptide has a free ammoniumgroup, while the carboxy terminus (C termi-nus) is formed by the carboxylate group of thelast amino acid. In peptides and proteins, theamino acid components are usually linked inlinear fashion. To express the sequence of apeptide, it is therefore suf cient to combinethe three-letter or single-letter abbreviationsfor the amino acid residues (see p. 60). Thissequence always starts at the N terminus. For
example, the peptide hormone angiotensin II(see p. 330) has the sequence Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, or DRVYIHPF.
D. Conformational space of the peptidechain �
With the exception of the terminal residues,every amino acid in a peptide is involved intwo peptide bonds (one with the precedingresidue and one with the following one). Dueto the restricted rotation around the C–Nbond, rotations are only possible around theN–Cα and Cα–C bonds (2). As mentionedabove, these rotations are described by thedihedral angles φ (phi) and ψ (psi). The angledescribes rotation around the N–Cα bond; ψdescribes rotation around Cα–C—i. e., the po-sition of the subsequent bond.
For steric reasons, only specific combina-tions of the dihedral angles are possible.These relationships can be illustrated clearlyby a so-called φ/ψ diagram (1). Most combi-nations of φ and ψ are sterically “forbidden”(red areas). For example, the combination φ =0° and ψ = 180° (4) would place the twocarbonyl oxygen atoms less than 115 pmapart—i. e., at a distance much smaller thanthe sum of their van der Waals radii (see p. 6).Similarly, in the case of φ = 180° and ψ = 0° (5),the two NH hydrogen atoms would collide.The combinations located within the greenareas are the only ones that are stericallyfeasible (e. g., 2 and 3). The important secon-dary structures that are discussed in the fol-lowing pages are also located in these areas.The conformations located in the yellow areasare energetically less favorable, but still pos-sible.
The φ/ψ diagram (also known as a Rama-chandran plot) was developed from modelingstudies of small peptides. However, the con-formations of most of the amino acids in pro-teins are also located in the permitted areas.The corresponding data for the small protein,insulin (see p. 76), are represented by blackdots in 1.
66 Biomolecules
180
120
60
ψ 0
-60
-120
-180 -120 -60 0 60 120 180
ϕ
A-9 B-20B-8
αr
βp
βaC
B-23
αl
2.
3.
4.
5.
ϕ
ψ
2 R
13
R3
1
ϕψ2
R
ϕ
ψ
1
3
2
ϕψ
R
2
1 31.
C N
H
O
C N
H
O
C N
H
O
ϕ ψ
H3NC
CN
CC
NC
CN
CC
NC
COO
R1
O
H
R2
O
H
R3
O
H
R4
O
H
Rn
HHH
H H
C N
H
O
C N
O
H
C N
O
H
A. Peptide bonds
C. Peptide nomenclature
Residue 1 Residue 2 Residue 3 Residue 4 Residue
Aminoterminus(N terminus)
Carboxy- terminus(C terminus)
B. Resonance
Resonancestructures
Mesomericstructure
Seryl alanine(Ser-Ala, H3N-Ser-Ala-COO , SA)
D. Conformation space of the peptide chain
ϕ (Phi): Rotation aboutj (Phi): N – Cαψ (Psi): Rotation abouty (Psi): Cα – C
Allowed Forbidden
ϕ = 0°ψ = 180°
d = 115 pm
ϕ = -139°ψ = -135°
ϕ = 180°ψ = 0°
d =155 pm
ϕ = -57°ψ = -47°
Collagen helixC
Pleated sheet (antiparallel)
Pleated sheet (parallel)
αr
αl
α Helix (right-handed)
α Helix (left-handed)
βa
βp
67Peptides and Proteins
Secondary structures
In proteins, specific combinations of the dihe-dral angles φ and ψ (see p. 66) are much morecommon than others. When several succes-sive residues adopt one of these conforma-tions, defined secondary structures arise,which are stabilized by hydrogen bonds ei-ther within the peptide chain or betweenneighboring chains. When a large part of aprotein takes on a defined secondary struc-ture, the protein often forms mechanicallystable filaments or fibers. Structural proteinsof this type (see p. 70) usually have character-istic amino acid compositions.
The most important secondary structuralelements of proteins are discussed here first.The illustrations only show the course of thepeptide chain; the side chains are omitted. Tomake the course of the chains clearer, thelevels of the peptide bonds are shown asblue planes. The dihedral angles of the struc-tures shown here are also marked in diagramD1 on p. 67.
A. -Helix �
The right-handed α-helix (αR) is one of themost common secondary structures. In thisconformation, the peptide chain is woundlike a screw. Each turn of the screw (the screwaxis in shown in orange) covers approxi-mately 3.6 amino acid residues. The pitch ofthe screw (i. e., the smallest distance betweentwo equivalent points) is 0.54 nm. α-Helicesare stabilized by almost linear hydrogen bondsbetween the NH and CO groups of residues,which are four positions apart from each an-other in the sequence (indicated by red dots;see p. 6). In longer helices, most amino acidresidues thus enter into two H bonds. Apolaror amphipathic α-helices with five to seventurns often serve to anchor proteins in bio-logical membranes (transmembrane helices;see p. 214).
The mirror image of the αR helix, the left-handed -helix (αL), is rarely found in nature,although it would be energetically “permissi-ble.”
B. Collagen helix �
Another type of helix occurs in the collagens,which are important constituents of the con-nectivetissue matrix (see pp. 70, 344). Thecollagen helix is left-handed, and with a pitchof 0.96 nm and 3.3 residues per turn, it issteeper than the α-helix. In contrast to theα-helix, H bonds are not possible within thecollagen helix. However, the conformation isstabilized by the association of three helicesto form a righthanded collagen triple helix(see p. 70).
C. Pleated-sheet structures �
Two additional, almost stretched, conforma-tions of the peptide chain are known aspleated sheets, as the peptide planes are ar-ranged like a regularly folded sheet of paper.Again, H bonds can only form between neigh-boring chains (“strands”) in pleated sheets.When the two strands run in opposite direc-tions (1), the structure is referred to as anantiparallel pleated sheet (βa). When theyrun in the same direction (2), it is a parallelpleated sheet (βp). In both cases, the α-Catoms occupy the highest and lowest pointsin the structure, and the side chains pointalternately straight up or straight down (seep. 71 C). The βa structure, with its almost lin-ear H bonds, is energetically more favorable.In extended pleated sheets, the individualstrands of the sheet are usually not parallel,but twisted relative to one another (see p. 74).
D. Turns �
Turns are often found at sites where thepeptide chain changes direction. These aresections in which four amino acid residuesare arranged in such a way that the courseof the chain reverses by about 180° into theopposite direction. The two turns shown(types I and II) are particularly frequent.Both are stabilized by hydrogen bonds be-tween residues 1 and 4. β Turns are oftenlocated between the individual strands ofantiparallel pleated sheets, or betweenstrands of pleated sheets and α helices.
68 Biomolecules
N C N C
N
C
N
C
A. α Helix B. Collagen helix
1. Type I 2. Type II
1. Antiparallel 2. Parallelϕ = –139˚ψ = +135˚
ϕ = –119˚ψ = +113˚
D. β Turns
C. Pleated-sheet structures
0.54
nm
0.15
nm
ϕ = –57˚ψ = –47˚
0.96
nm
0.29
nm
–80˚ < ϕ < –50˚+130˚ < ψ < +155˚
69Peptides and Proteins
Structural proteins
The structural proteins give extracellularstructures mechanical stability, and are in-volved in the structure of the cytoskeleton(see p. 204). Most of these proteins contain ahigh percentage of specific secondary struc-tures (see p. 68). For this reason, the aminoacid composition of many structural proteinsis also characteristic (see below).
A. Keratin �
-Keratin is a structural protein that predom-inantly consists of α helices. Hair (wool),feathers, nails, claws and the hooves of ani-mals consist largely of keratin. It is also animportant component of the cytoskeleton(cytokeratin), where it appears in intermedi-ate filaments (see p. 204).
In the keratins, large parts of the peptidechain show right-handed α-helical coiling.Two chains each form a left-handed super-helix, as is also seen in myosin (see p. 65).The superhelical keratin dimers join to formtetramers, and these aggregate further toform protofilaments, with a diameter of3 nm. Finally, eight protofilaments thenform an intermediate filament, with a diam-eter of 10 nm (see p. 204).
Similar keratin filaments are found in hair.In a single wool fiber with a diameter of about20 µm, millions of filaments are bundled to-gether within dead cells. The individual kera-tin helices are cross-linked and stabilized bynumerous disulfide bonds (see p. 72). This factis exploited in the perming of hair. Initially,the disulfide bonds of hair keratin are dis-rupted by reduction with thiol compounds(see p. 8). The hair is then styled in the desiredshape and heat-dried. In the process, newdisulfide bonds are formed by oxidation,which maintain the hairstyle for some time.
B. Collagen �
Collagen is the quantitatively most importantprotein in mammals, making up about 25% ofthe total protein. There are many differenttypes of collagen, particularly in connectivetissue. Collagen has an unusual amino acidcomposition. Approximately one-third of theamino acids are glycine (Gly), about 10% pro-line (Pro), and 10% hydroxyproline (Hyp). The
two latter amino acids are only formed duringcollagen biosynthesis as a result of posttrans-lational modification (see p. 344).
The triplet Gly-X-Y (2) is constantly re-peated in the sequence of collagen, with theX position often being occupied by Pro andthe Y position by Hyp. The reason for this isthat collagen is largely present as a triple helixmade up of three individual collagen helices(1). In triple helices, every third residue lieson the inside of the molecule, where for stericreasons there is only room for glycine resi-dues (3; the glycine residues are shown inyellow). Only a small section of a triple helixis illustrated here. The complete collagenmolecule is approximately 300 nm long.
C. Silk fibroin �
Silk is produced from the spun threads fromsilkworms (the larvae of the moth Bombyxmori and related species). The main proteinin silk, fibroin, consists of antiparallel pleatedsheet structures arranged one on top of theother in numerous layers (1). Since the aminoacid side chains in pleated sheets point eitherstraight up or straight down (see p. 68), onlycompact side chains fit between the layers. Infact, more than 80% of fibroin consists of gly-cine, alanine, and serine, the three aminoacids with the shortest side chains. A typicalrepetitive amino acid sequence is (Gly-Ala-Gly-Ala-Gly-Ser). The individual pleated sheetlayers in fibroin are found to lie alternately0.35 nm and 0.57 nm apart. In the first case,only glycine residues (R = H) are opposed toone another. The slightly greater distance of0.57 nm results from repulsion forces be-tween the side chains of alanine and serineresidues (2).
70 Biomolecules
Ala
Gly
Ala
Gly
Ala Ala
Gly Gly
GlyGly
SerAla
Gly
Gly
Gly
Gly
Gly
Gly
Arg
Gln
Pro
Pro
Ala
X
Hyp
Arg
Hyp
Gln
Arg
Y
Gly
3 nm
10 nm
A. α-Keratin
C. Silk fibroin
Left-handedsuperhelix
Right-handedα helix
Intermediaryfilament
Protofilament
1. Spatial illustration
B. Collagen
1. Triple helix (section)
2. Front view
0.35
nm
0.57
nm
3. Triple helix(view from above)
2. Typical sequence
71Peptides and Proteins
Globular proteins
Soluble proteins have a more complex struc-ture than the fibrous, completely insolublestructural proteins. The shape of soluble pro-teins is more or less spherical (globular). Intheir biologically active form, globularproteins have a defined spatial structure(the native conformation). If this structure isdestroyed (denaturation; see p. 74), not onlydoes the biological effect disappear, but theprotein also usually precipitates in insolubleform. This happens, for example, when eggsare boiled; the proteins dissolved in the eggwhite are denatured by the heat and producethe solid egg white.
To illustrate protein conformations in aclear (but extremely simplified) way, Richard-son diagrams are often used. In thesediagrams, α-helices are symbolized by redcylinders or spirals and strands of pleatedsheets by green arrows. Less structured areasof the chain, including the β-turns, are shownas sections of gray tubing.
A. Conformation-stabilizing interactions �
The native conformation of proteins is stabi-lized by a number of different interactions.Among these, only the disulfide bonds (B)represent covalent bonds. Hydrogen bonds,which can form inside secondary structures,as well as between more distant residues, areinvolved in all proteins (see p. 6). Many pro-teins are also stabilized by complex formationwith metal ions (see pp. 76, 342, and 378, forexample). The hydrophobic effect is particu-larly important for protein stability. In glob-ular proteins, most hydrophobic amino acidresidues are arranged in the interior of thestructure in the native conformation, whilethe polar amino acids are mainly found onthe surface (see pp. 28, 76).
B. Disulfide bonds �
Disulfide bonds arise when the SH groups oftwo cysteine residues are covalently linked asa dithiol by oxidation. Bonds of this type areonly found (with a few exceptions) in extra-cellular proteins, because in the interior of thecell glutathione (see p. 284) and other reduc-ing compounds are present in such high con-centrations that disulfides would be reduc-
tively cleaved again. The small plant proteincrambin (46 amino acids) contains three di-sulfide bonds and is therefore very stable. Thehigh degree of stability of insulin (see p. 76)has a similar reason.
C. Protein dynamics �
The conformations of globular proteins arenot rigid, but can change dramatically onbinding of ligands or in contact with otherproteins. For example, the enzyme adenylatekinase (see p. 336) has a mobile domain (do-main = independently folded partial struc-ture), which folds shut after binding of thesubstrate (yellow). The larger domain (bot-tom) also markedly alters its conformation.There are large numbers of allostericproteins of this type. This group includes, forexample, hemoglobin (see p. 280), calmodulin(see p. 386), and many allosteric enzymessuch as aspartate carbamoyltransferase (seep.116).
D. Folding patterns �
The globular proteins show a high degree ofvariability in folding of their peptide chains.Only a few examples are shown here. Purelyhelically folded proteins such as myoglobin (1;see p. 74, heme yellow) are rare. In general,pleated sheet and helical elements existalongside each other. In the hormone-bindingdomain of the estrogen receptor (2; see p. 378),a small, two-stranded pleated sheet functionsas a “cover” for the hormone binding site(estradiol yellow). In flavodoxin, a small flavo-protein with a redox function (3; FMN yel-low), a fan-shaped, pleated sheet made up offive parallel strands forms the core of themolecule. The conformation of the β subunitof the G-protein transducin (4; see pp. 224,358) is very unusual. Seven pleated sheetsform a large, symmetrical “β propeller.” TheN-terminal section of the protein contains onelong and one short helix.
72 Biomolecules
S
NH
CO
SS
C O
N H
CH2HC CH2 CH
A. Conformation-stabilizing interactions
C. Protein dynamics
D. Folding patterns
4. Transducin (β subunit)
B. Disulfide bonds
1. Myoglobin
2. Estrogen receptor (domain)
3. Flavodoxin
Polar surface
Apolar core
Disulfidebond
Metalcomplex
Hydrogen bond
Mobile domain
Adenylate kinase
Substrate
73Peptides and Proteins