Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins Chapter 26: Biomolecules: Amino Acids,

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Transcript of Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins Chapter 26: Biomolecules: Amino Acids,

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    348

    Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins

    monomer unit: α-amino acids biopolymer: peptide (< 50 amino acids)

    protein (> 50 amino acids)

    R CO2H

    NH2H

    !- Amino Acid

    R = sidechain

    Peptide or protein

    N H

    O

    R3

    H N

    O

    R2

    N H

    O

    R1

    H N

    N H

    O

    R7

    H N

    O

    R6

    N H

    O

    R5

    R4 H N

    O

    Amino acids are linked together through amide bonds (peptide bonds)

    349

    26.1 Structures of Amino Acids Amino acids exist as a zwitterion: a dipolar ion having

    both a formal positive and formal negative charge (overall charge neutral); internal salts

    CO2H

    R

    H

    H2N CO2

    R

    H

    H3N _+

    Amino acids are amphoteric: they can react as either an acid or a base. Ammonium ion acts as an acid, the carboxylate as a base

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    350

    20 common amino acids 19 are 1°-amines, one (proline) is a 2°-amine

    19 amino acids are “chiral; one (glycine) is achiral (R=H)

    The configuration “natural” amino acid is L 19 are of the S stereochemistry, one (cysteine) is R

    R CO2H

    NH2H

    R = sidechain

    primary α-amino acid

    N CO2 _

    H H

    +

    proline secondary α-amino acid

    CHO

    CH2OH

    H OH

    D-glyceraldehyde

    CHO

    CH2OH

    HO H

    L-glyceraldehyde

    CO2H

    CH3

    H2N H

    CO2H

    CH2SH

    H2N H

    L-alanine L-cysteine

    351

    Neutral amino acids

    (S)-(+)-Valine (Val, V)(S)-(–)-Tryptophan (Trp, W)

    (S)-(–)-Proline (Pro, P)(S)-(–)-Phenylalanine (Phe, F)

    COO–

    NH3

    H

    N

    H

    COO–

    NH3

    COO–

    NH3

    COO–

    NH3

    NH3

    COO–

    COO–

    (2S,3S)-(+)-Isoleucine (Ile, I)

    (S)-(+)-Alanine (Ala, A)

    (S)-(–)-Leucine (Leu, L)

    NH3

    COO–S

    (S)-(–)-Methionine (Met, M)

    (S)-(+)-Glutamine (Gln, Q)

    Glycine (Gly, G)

    NH3

    COO–

    H2N

    O

    NH3

    COO–

    (S)-(–)-Tyrosine (Tyr, Y)

    (2S,3R)-(–)-Threonine (Thr, T)(S)-(–)-Serine (Ser, S)

    COO–

    NH3

    COO–

    NH3

    COO–

    NH3 NH3

    COO–

    NH3

    COO–

    O

    H2N HS

    HO

    OH

    HO

    (R)-(–)-Cysteine (Cys, C)(S)-(–)-Asparagine (Asn, N)

    pKa ~ 13 pKa ~ 13

    pKa ~ 8.2

    pKa ~ 10.1

    COO–

    NH3N H

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    352

    Acidic amino acids

    Basic amino acids

    (S)-(–)-Histidine (His, H)

    NH3

    COO– COO–

    NH3 NH3

    COO– N

    H

    N N

    H

    H

    (S)-(+)-Lysine (Lys, K) (S)-(+)-Arginine (Arg, R)

    pKa ~ 10.5 pKa ~ 6.0 pKa ~ 12.5

    H2N

    N H H

    H3N

    -O

    O NH3

    COO–

    (S)-(+)-Aspartic Acid (Asp, D)

    COO–

    NH3

    O

    -O

    (S)-(+)-Glutamic Acid (Glu, E)

    pKa ~ 3.6 pKa ~ 4.2

    353

    Humans can produce (biosynthesize) ten of the twenty amino acids; the remaining ten must be obtained by diet and are called essential amino acids: tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine and isoleucine.

    26.2 Isoelectric points pI: pH at which the amino acid exists largely in a neutral, zwitterionic form (influenced by the nature of the sidechain)

    CO2H

    R

    H

    H2N CO2

    R

    H

    H3N _+

    CO2H

    R

    H

    H3N +H3O

    +

    pKa1

    CO2

    R

    H

    H2N

    HO _

    pKa2

    low pH

    high pH

    _

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    354

    pI = pKax + pKay

    2

    pI = pKa1 + pKa2

    2

    pI = pKa1 + pKa3

    2

    pI = pKa2 + pKa3

    2

    pI = 9.7

    pI = 2.7

    CO2

    CH3

    H

    H3NCO2H

    CH3

    H

    H3N

    low pH

    CO2

    CH3

    H

    H2N + +

    high pH

    pKa1 (2.3)

    pKa2 (9.7)

    pI = 6.0

    CO2H

    (CH2)4

    H

    H3N

    NH3

    pKa2 (9.0)

    CO2

    H

    H3N

    (CH2)4

    NH3

    CO2

    H

    H2N

    (CH2)4

    NH3

    pKa3 (10.5)

    pKa1 (2.2)

    CO2

    H

    H2N

    (CH2)4

    NH2

    low pH high pH

    CO2H

    CH2

    H

    H3N

    CO2H

    pKa3 (3.6)

    CO2

    H

    H3N

    CH2

    CO2H

    CO2

    H

    H3N

    CH2

    CO2

    pKa2 (9.6)

    pKa1 (1.9)

    CO2

    H

    H2N

    CH2

    CO2

    low pH high pH

    355

    Henderson-Hasselbalch equation: allows the calculation of the relative amounts of the protonated, neutral, and deprotonated forms at a given pH from the pKa values of the amino acid (please read)

    Electrophoresis: separation of polar compounds based on their mobility through a solid support. The separation is based on charge (pI) or molecular mass.

    + _

    _ _ _ _ + + + +

    + _

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    26.3 Synthesis of Amino Acids From Chapter 24: HVZ reaction followed by SN2 reaction

    with NH3 or ammonia equivalents

    Reductive amination

    R-CH2-CO2H

    R C CO2H

    Br

    R C CO2H

    NH2

    R C CO2H

    N3

    Br2, PBr3

    NH3 NaN3

    H2, Pd/C

    R C CO2H

    N OO KOH, H2O

    N

    O

    O

    K H

    H

    H

    C CO2HR

    O NH3

    H2, Pd/C -or-

    NaB(CN)H3

    C CO2HR

    NH2

    H

    357

    RCH2 CO2Et C

    CO2EtHN EtO Na

    RCH2X

    H3O

    - CO2 RCH2 CO2H C

    HH2N

    O

    RCH2 CO2Et C

    CO2EtHN

    O

    Amidomalonate Synthesis

    26.4 Enantioselective Synthesis of Amino Acids The syntheses in the previous section give racemic products!!

    R-CH2-CO2H

    Br2, PBr3

    RCH Br

    O

    Br Br

    R C H

    CO2H

    Br

    R

    H O

    Br

    Br Br

    Br Br

    Br

    R

    H CO2H

    Br

    R

    H CO2H

    R

    S

    50:50 mixture of

    enantiomers

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    358

    Resolution: separation of enantiomers

    RCH2 CO2H C

    NH2H

    N

    N

    H

    H

    (-)-sparteine (chiral base)

    RCH2 CO2

    C

    NH2H

    N

    N

    H

    H H

    N

    N

    H

    H H

    RCH2 CO2

    C

    HH2N

    +

    Diastereomeric salts (separate)

    H3O H3O

    RCH2 CO2

    C

    NH3H

    RCH2 CO2

    C

    HH3N

    racemic

    Resolutions are inherently inefficient

    359

    Enantioselective Synthesis of Amino Acids (please read)

    R

    H CO2H

    NHAc

    H H

    H H

    R NHAc

    H H

    H CO2H

    R NHAc

    H H

    H CO2H R

    S

    Rh(I) L*, H2

    O

    O

    CO2Me

    HO

    OH

    CO2

    NH3

    L-DOPA

    O

    O

    CO2Me

    HN

    O

    PhHN

    O

    Ph

    H3O +

    Chiral hydrogenation catalysts can differentiate the faces of the C=C double bond leading a products that is highly enriched in one enantiomer.

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    26.5 Peptides and Proteins Proteins and peptides are polymers made up of amino acid units

    (residues) that are linked together through the formation of an amide bonds (peptide bonds) from the amino group of one residue and the carboxylate of a second residue

    By convention, peptide sequences are written left to right from the N-terminus to the C-terminus

    H2N CO2H

    Alanine

    H2N CO2H

    HO

    Serine

    + - H2O H2N

    H N

    O

    CO2H

    OH

    Ala - Ser (A - S)- H2O

    H2N

    H N

    O

    CO2H

    HO

    Ser - Ala (S - A)

    C-terminus

    N-terminus

    C-terminus

    N-terminus

    N H

    O

    R3

    H N

    O

    R2

    N H

    O

    R1

    H N

    N H

    O

    R7

    H N

    O

    R6

    N H

    O

    R5

    R4 H N

    O

    backbone

    361

    26.6 Covalent Bonding in Peptides I. The amide bond

    II. Disulfide bonds: the thiol groups of cysteine can be oxidized to form disulfides (Cys-S-S-Cys)

    C=N double bond character due to this resonance structure

    restricts rotations resistant to hydrolysis

    R1

    H N

    N

    O R2 H N

    O

    amide bond

    R1

    H N

    N

    O R2 H N

    O

    _

    +

    H H

    SH HO2C

    NH2 2

    1/2 O2 H2O

    S HO2C

    NH2

    S CO2H

    NH2

    N H

    O

    R2

    H N

    O

    R1

    N H

    H N

    O

    R5

    N H

    O

    R4

    H N

    O

    N H

    O H N

    O

    R6

    N H

    H N

    O

    R10

    N H

    O

    R9

    R8 H N

    O

    SH

    N H

    O

    R2

    H N

    O