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Amino Acids & Proteins Ghollam-Reza Moshtaghi-Kashanian Biochemistry Department Medical School Kerman University of Medical sciences.

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Presentation on theme: "Amino Acids & Proteins Ghollam-Reza Moshtaghi-Kashanian Biochemistry Department Medical School Kerman University of Medical sciences."— Presentation transcript:

1 Amino Acids & Proteins Ghollam-Reza Moshtaghi-Kashanian Biochemistry Department Medical School Kerman University of Medical sciences

2 Introduction Most biologically important macromolecules are polymers, called biopolymers. Biopolymers fall into three classes: –polysaccharides (carbohydrates), –proteins, –nucleic acids.

3 Proteins Amino Acids Proteins are large molecules present in all cells. They are made up of  -amino acids. There are two forms of an amino acid: one that is neutral (with -NH 2 and -COOH groups) and one that is zwitterionic (with -NH 3 + and -COO - groups). A zwitterion has both positive and negative charge in one molecule. There are about 20 amino acids found in most proteins.

4 Structure and Properties of Amino-acids, Protein Primary Structure - Proteins are polymers made out by the condensation of amino-acids -strings of amino-acids are called polypeptide chains. -There are 20 different chemical kinds of natural amino- acids plus some special variants. -Each protein has a specific sequence of amino-acids (primary structure), which is determined by the DNA sequence of the gene encoding for the protein.

5 Structure and Properties of Amino-acids, Protein Primary Structure -Proteins with the same function from different organisms have similar primary structures -Amino-acid sequence determines the 3-D structure in which the protein folds and its biological function. -Proteins can have very different sizes (from 30 to ~ 100,000 residues) -The basic module in primary sequence is the protein domain

6 Structure and Properties of Amino-acids, Protein Primary Structure -some proteins are monodomain others are multidomain in one chain -some proteins are composed by more than one polypeptide chain -Proteins can be characterized spectroscopically -Proteins can be isolated and purified based on their differential chemical and physical properties

7 Amino Acids

8 Fundamentals While their name implies that amino acids are compounds that contain an —NH 2 group and a —CO 2 H group, these groups are actually present as —NH 3 + and —CO 2 – respectively. They are classified as , , , etc. amino acids according the carbon that bears the nitrogen.

9 Amino Acids NH3NH3NH3NH3+ CO2CO2CO2CO2 – an  -amino acid that is an intermediate in the biosynthesis of ethylene + H 3 NCH 2 CH 2 CO 2 – a  -amino acid that is one of the structural units present in coenzyme A + H 3 NCH 2 CH 2 CH 2 CO 2 – a  -amino acid involved in the transmission of nerve impulses   

10 The 20 (22) Key Amino Acids More than 700 amino acids occur naturally, but 20 (22?)of them are especially important. These 22 amino acids are the building blocks of proteins. All are  -amino acids. They differ in respect to the group attached to the  carbon.

11 Amino Acids CCOO – RR H H3NH3NH3NH3N + The amino acids obtained by hydrolysis of proteins differ in respect to R (the side chain). The properties of the amino acid vary as the structure of R varies.

12 Amino Acids CCOO – H H H3NH3NH3NH3N + Glycine is the simplest amino acid. It is the only one in the table that is achiral. In all of the other amino acids in the table the  carbon is a stereogenic center. Glycine (Gly or G)

13 Glycine (Gly or G)

14 Amino Acids CC O O – CH 3 H H3NH3NH3NH3N + Alanine (Ala or A)

15 Alanine (Ala or A)

16 Amino Acids CC O O – CH(CH 3 ) 2 H H3NH3NH3NH3N + Valine (Val or V)

17 Valine (Val or V)

18 Amino Acids CC O O – CH 2 CH(CH 3 ) 2 H H3NH3NH3NH3N + Leucine (Leu or L)

19 Leucine (Leu or L)

20 Amino Acids CC O O – CH 3 CHCH 2 CH 3 H H3NH3NH3NH3N + Isoleucine (Ile or I)

21 Isoleucine (Ile or I)

22 Amino Acids CC O O – CH 2 OH H H3NH3NH3NH3N + Serine (Ser or S)

23 Serine (Ser or S)

24 Amino Acids CC O O – CH 3 CHOH H H3NH3NH3NH3N + Threonine (Thr or T)

25 Threonine (Thr or T)

26 Amino Acids CC O O – CH 3 SCH 2 CH 2 H H3NH3NH3NH3N + Methionine (Met or M)

27 Methionine (Met or M)

28 Amino Acids CC O O – CH 2 SH H H3NH3NH3NH3N + Cysteine (Cys or C)

29 Cysteine (Cys or C)

30 Amino Acids Aspartic Acid CCOO – H H3NH3NH3NH3N + OCCH 2 O – (Asp or D)

31 Aspartic Acid (Asp or D)

32 Amino Acids Asparagine CCOO – H H3NH3NH3NH3N + H 2 NCCH 2 O (Asn or N)

33 Asparagine (Asn or N)

34 Amino Acids Glutamic Acid CCOO – H H3NH3NH3NH3N + OCCH 2 CH 2 O – (Glu or E)

35 Glutamic Acid (Glu or E)

36 Amino Acids Glutamine CCOO – H H3NH3NH3NH3N + H 2 NCCH 2 CH 2 O (Gln or Q)

37 Glutamine (Gln or Q)

38 Amino Acids CC O O – CH 2 CH 2 CH 2 NHCNH 2 H H3NH3NH3NH3N + Arginine + NH2NH2NH2NH2 (Arg or R)

39 Arginine (Arg or R)

40 Amino Acids CC O O – CH 2 CH 2 CH 2 CH 2 NH 3 H H3NH3NH3NH3N + Lysine + (Lys or K)

41 Lysine (Lys or K)

42 Amino Acids Proline CCOO – CH 2 H H2NH2NH2NH2N + H2CH2CH2CH2C CH2CH2CH2CH2 (Pro or P)

43 Proline (Pro or P)

44 Amino Acids Phenylalanine CCOO – CH 2 H H3NH3NH3NH3N + (Phe or F)

45 Phenylalanine (Phe or F)

46 Amino Acids Tyrosine CCOO – CH 2 H H3NH3NH3NH3N + OH (Tyr or Y)

47 Tyrosine (Tyr or Y)

48 Amino Acids Tryptophan CCOO – CH 2 H H3NH3NH3NH3N + N H (Trp or W)

49 Tryptophan (Trp or W)

50 Amino Acids Histidine CC O O – H H3NH3NH3NH3N + CH 2 NH N (His or H)

51 Histidine (His or H)

52 Amino Acids: Selenocysteine

53 Selenocysteine

54 Pyrrolysine (4 R, 5 R)

55 Pyrrolysine

56 Amino Acids: Pyrrolysine

57 Acid-Base Behavior of Amino Acids

58 Amino Acids While their name implies that amino acids are compounds that contain an —NH 2 group and a —CO 2 H group, these groups are actually present as —NH 3 + and —CO 2 – respectively. How do we know this?

59 Properties of Glycine OOH H 2 NCH 2 C – OO H 3 NCH 2 C + The properties of glycine: high melting point (when heated to 233°C it decomposes before it melts) solubility: soluble in water; not soluble in nonpolar solvent more consistent with this than this

60 Properties of Glycine – OO H 3 NCH 2 C + The properties of glycine: high melting point (when heated to 233°C it decomposes before it melts) solubility: soluble in water; not soluble in nonpolar solvent more consistent with this called a zwitterion or dipolar ion

61 Acid-Base Properties of Glycine The zwitterionic structure of glycine also follows from considering its acid-base properties. A good way to think about this is to start with the structure of glycine in strongly acidic solution, say pH = 1. At pH = 1, glycine exists in its protonated form (a monocation).

62 Acid-Base Properties of Glycine The zwitterionic structure of glycine also follows from considering its acid-base properties. A good way to think about this is to start with the structure of glycine in strongly acidic solution, say pH = 1. At pH = 1, glycine exists in its protonated form (a monocation). OOH H 3 NCH 2 C +

63 Acid-Base Properties of Glycine Now ask yourself "As the pH is raised, which is the first proton to be removed? Is it the proton attached to the positively charged nitrogen, or is it the proton of the carboxyl group?" You can choose between them by estimating their respective pK a s. OOH H 3 NCH 2 C +

64 Acid-Base Properties of Glycine Now ask yourself "As the pH is raised, which is the first proton to be removed? Is it the proton attached to the positively charged nitrogen, or is it the proton of the carboxyl group?" You can choose between them by estimating their respective pK a s. OOH H 3 NCH 2 C + typical ammonium ion: pK a ~9 typical carboxylic acid: pK a ~5

65 Acid-Base Properties of Glycine The more acidic proton belongs to the CO 2 H group. It is the first one removed as the pH is raised. OOH H 3 NCH 2 C + typical carboxylic acid: pK a ~5

66 Acid-Base Properties of Glycine Therefore, the more stable neutral form of glycine is the zwitterion. OOH H 3 NCH 2 C + typical carboxylic acid: pK a ~5 – OO H 3 NCH 2 C +

67 The measured pK a of glycine is Glycine is stronger than a typical carboxylic acid because the positively charged N acts as an electron-withdrawing, acid-strengthening substituent on the  carbon. Acid-Base Properties of Glycine OOH H 3 NCH 2 C + typical carboxylic acid: pK a ~5

68 Acid-Base Properties of Glycine – OO H 3 NCH 2 C + The pK a for removal of this proton is This value is about the same as that for NH 4 + HO– – OO H 2 NCH 2 C A proton attached to N in the zwitterionic form of nitrogen can be removed as the pH is increased further.

69 Isoelectric Point pI – OO H 3 NCH 2 C + – OO H 2 NCH 2 C OOH H 3 NCH 2 C + pK a = 2.34 pK a = 9.60 The pH at which the concentration of the zwitterion is a maximum is called the isoelectric point. Its numerical value is the average of the two pK a s. The pI of glycine is 5.97.

70 Acid-Base Properties of Amino Acids One way in which amino acids differ is in respect to their acid-base properties. This is the basis for certain experimental methods for separating and identifying them. Just as important, the difference in acid-base properties among various side chains affects the properties of the proteins that contain them.

71 Amino Acids with Neutral Side Chains CCOO – H H H3NH3NH3NH3N + Glycine pK a1 = 2.34 pK a2 =9.60 pI =5.97

72 Amino Acids with Neutral Side Chains Alanine pK a1 = 2.34 pK a2 =9.69 pI =6.00 H3NH3NH3NH3N CCOO – CH 3 H +

73 Amino Acids with Neutral Side Chains Valine pK a1 = 2.32 pK a2 =9.62 pI =5.96 H3NH3NH3NH3N CCOO – CH(CH 3 ) 2 H +

74 Amino Acids with Neutral Side Chains Leucine pK a1 = 2.36 pK a2 =9.60 pI =5.98 H3NH3NH3NH3N CCOO – CH 2 CH(CH 3 ) 2 H +

75 Amino Acids with Neutral Side Chains Isoleucine pK a1 = 2.36 pK a2 =9.60 pI =5.98 H3NH3NH3NH3N CC O O – CH 3 CHCH 2 CH 3 H +

76 Amino Acids with Neutral Side Chains Methionine pK a1 = 2.28 pK a2 =9.21 pI =5.74 H3NH3NH3NH3N CC O O – CH 3 SCH 2 CH 2 H +

77 Amino Acids with Neutral Side Chains Proline pK a1 = 1.99 pK a2 =10.60 pI =6.30 H2NH2NH2NH2N CCOO – H + CH 2 H2CH2CH2CH2C CH2CH2CH2CH2

78 Side Chains Phenylalanine pK a1 = 1.83 pK a2 =9.13 pI =5.48 H3NH3NH3NH3N CCOO – H + CH 2

79 Amino Acids with Neutral Side Chains Tryptophan pK a1 = 2.83 pK a2 =9.39 pI =5.89 H3NH3NH3NH3N CCOO – H + CH 2 H N

80 Amino Acids with Neutral Side Chains Asparagine pK a1 = 2.02 pK a2 =8.80 pI =5.41 H3NH3NH3NH3N CC O O – H + H 2 NCCH 2 O

81 Amino Acids with Neutral Side Chains Glutamine pK a1 = 2.17 pK a2 =9.13 pI =5.65 H3NH3NH3NH3N CCOO – H + H 2 NCCH 2 CH 2 O

82 Amino Acids with Neutral Side Chains Amino Acids with Neutral Side Chains Serine pK a1 = 2.21 pK a2 =9.15 pI =5.68 H3NH3NH3NH3N CCOO – CH 2 OH H +

83 Amino Acids with Neutral Side Chains Threonine pK a1 = 2.09 pK a2 =9.10 pI =5.60 H3NH3NH3NH3N CC O O – CH 3 CHOH H +

84 Amino Acids with Ionizable Side Chains Aspartic acid pK a1 = 1.88 pK a2 =3.65 pK a3 =9.60 pI =2.77 H3NH3NH3NH3N CC O O – H + OCCH 2 O– For amino acids with acidic side chains, pI is the average of pK a1 and pK a2.

85 Amino Acids with Ionizable Side Chains Glutamic acid pK a1 = 2.19 pK a2 =4.25 pK a3 =9.67 pI =3.22 H3NH3NH3NH3N CC O O – H + O OCCH 2 CH 2 –

86 Amino Acids with Ionizable Side Chains Tyrosine pK a1 = 2.20 pK a2 =9.11 pK a3 =10.07 pI =5.66 H3NH3NH3NH3N CCOO – H + CH 2 OH

87 Amino Acids with Ionizable Side Chains Cysteine H3NH3NH3NH3N CCOO – CH 2 SH H + pK a1 = 1.96 pK a2 =8.18 pK a3 =10.28 pI =5.07

88 Amino Acids with Ionizable Side Chains Lysine pK a1 = 2.18 pK a2 =8.95 pK a3 =10.53 pI =9.74 H3NH3NH3NH3N CCOO – H + CH 2 CH 2 CH 2 CH 2 NH 3 + For amino acids with basic side chains, pI is the average of pK a2 and pK a3.

89 Amino Acids with Ionizable Side Chains Arginine pK a1 = 2.17 pK a2 =9.04 pK a3 =12.48 pI =10.76 H3NH3NH3NH3N CCOO – H + CH 2 CH 2 CH 2 NHCNH 2 + NH2NH2NH2NH2

90 Amino Acids with Ionizable Side Chains Histidine pK a1 = 1.82 pK a2 =6.00 pK a3 =9.17 pI =7.59 H3NH3NH3NH3N CCOO – H + CH 2 NH N

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92 Stereochemistry of Amino Acids

93 Configuration of  -Amino Acids Glycine is achiral. All of the other amino acids in proteins have the L -configuration at their  carbon. H3NH3NH3NH3N + H R CO 2 –

94 Proteins Amino Acids Our bodies can synthesize about 10 amino acids. Essential amino acids are the other 10 amino acids, which have to be ingested. The  -carbon in all amino acids except glycine is chiral (has 4 different groups attached to it). Chiral molecules exist as two non-superimposable mirror images. The two mirror images are called enantiomers. Chiral molecules can rotate the plane of polarized light.

95 Proteins Amino Acids

96 Proteins

97 Proteins The enantiomer that rotates the plane of polarized light to the left is called L- (laevus = “left”) and the other enantiomer is called D- (dexter = right). Enantiomers have identical physical and chemical properties. They only differ in their interaction with other enantiomers. Most amino acids in proteins exist in the L-form.

98 Proteins Polypeptides and Proteins Proteins are polyamides. When formed by amino acids, each amide group is called a peptide bond. Peptides are formed by condensation of the -COOH group of one amino acid and the NH group of another amino acid. The acid forming the peptide bond is named first. Example: if a dipeptide is formed from alanine and glycine so that the COOH group of glycine reacts with the NH group of alanine, then the dipeptide is called glycylalanine.

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101 Proteins Polypeptides and Proteins Glycylalanine is abbreviated gly-ala or GA. Polypeptides are formed with a large number of amino acids (usually result in proteins with molecular weights between 6000 and 50 million amu). Protein Structure Primary structure is the sequence of the amino acids in the protein. A change in one amino acid can alter the biochemical behavior of the protein.

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105 Protein Structure 1 o : The linear sequence of amino acids and disulfide bonds eg. ARDV:Ala. Arg. Asp. Val. 2 o : Local structures which include, folds, turns,  - helices and  -sheets held in place by hydrogen bonds. 3 o : 3-D arrangement of all atoms in a single polypeptide chain. 4 o : Arrangement of polypeptide chains into a functional protein, eg. hemoglobin.

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109 Enzymes Enzymes are proteins which act as biological catalysts. Over 1500 have been isolated. Human genome project scientists estimate that there are about 30,000 (>100,000) enzymes in a human. Active (catalytic) site is a crevice which binds a substrate. Lock & key metaphore....but, protein can change conformation. The active site is evolutionarily conserved.

110 Enzyme Inhibitors / Effectors Michaelis-Minton Kinetics E = Enzyme; S = Substrate Enzyme Activity is reduced by inhibitors. Four types of inhibitors: Reversible, Irreversible, Competitive, Non-competitive Equilibrium Constant & Free Energy K [ES]eq = to ; Free Energies -3 to -12 kcal/mol vs. covalent bonds -50 to -110 kcal/mol Effectors increase enzyme activity.


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