Globular Proteins

Myoglobin/Hemoglobin
Hemeproteins: group of specialized proteins that contain heme group as a tightly bound prosthetic group. prosthetic group: is a non-protein compound that is permanently associated with protein The role of heme group is dependent on the environment created

by the three-dimensional structure of the protein.

e.g. heme in cytochrome electron carrier, enzyme catalase active site

Myoglobin and hemoglobin Oxygen carrier

Myoglobin/Hemoglobin
First protein structures determined
Oxygen carriers

Hemoglobin transport O2 from lungs to tissues

Myoglobin O2 storage protein

8 alpha-helices Contain heme group

Mb and Hb subunits structurally similar

Mb monomeric protein Hb heterotetramer (22)

myoglobin hemoglobin

Hemoglobin A1c Under physiologic conditions HbA is slowly and non-enzymatically glycosylated The extent of glycosylation is dependent on the plasma level of particular hexoses The most abundant glycosylated Hb is HbA1c which has glucose unit that covalently linked to amino group of Nterminal valines of the beta chain In the case of Diabetes mellitus, the

amount of HbA1c will increase

Hemoglobinopathies Defined as a family of disorders caused either by production of structurally abnormal hemoglobin molecule, synthesis of insufficient quantities of normal hemoglobin or rarely both Sickle- cell anemia (HbS) Hemoglobin C disease (HbC) Thalassemia Sickle- cell anemia (Hemoglobin S disease HbS) a glutamate residue is replaced by valine residue in the -chains. This results in two fewer negative charges for the tetrameric structure. The substitution of a hydrophobic amino acid for a hydrophilic one makes the resulting molecule sticky. which causes molecules to stick together at this point. This causes aggregation to occur in deoxyhemoglobin. Subsequent to strand formation, several strands can assemble to form an insoluble fiber, which is what gives sickled cells there shape. People with sickle cell anemia suffer from repeated crises brought on by physical exertion.

Hemoglobinopathies

Sickle- cell anemia (Hemoglobin S disease HbS)

Hemoglobin C disease HbC is a hemoglobin variant having a single substitution in the sixth position of the -globin chain. In this case lysine is substituted. Patients have a relatively mild chronic hemolytic anemia and they don't suffer from infractive crises Thalassemias Thalassemia is a hereditary hemolytic disease in which an imbalance in the synthesis of globin chains occurs Normally the synthesis of -chains and -chains are coordinated so that each -globin has its -globin in the thalassemia the synthesis of either - or -globin chain is defective -thalassemia: defect in the synthesis of the -globin and there are 4 different levels of this type -thalassemia: -globin is decreased or absent, there are 2 different level of this type

Enzymes
Nearly all the reactions of the body are mediated by enzymes Enzymes are protein catalysts that increase the rate of the reactions without being changed in the overall process

Catalysts for biological reactions

Lower the activation energy. It will not affect the equilibrium but decrease the time required to reach the equilibrium
Increase the rate of reaction Activity lost if denatured May be simple proteins May contain cofactors such as metal ions or organic (vitamins)

Enzymes
Nomenclature of enzymes Enzyme has two names a. Short Recommended name b. Systemic name Recommended name End in ase, Identifies a reacting substance sucrase reacts sucrose lipase - reacts lipid Describes function of enzyme oxidase catalyzes oxidation hydrolase catalyzes hydrolysis lactate dehydrogenase, adenylate cyclase Common names of digestion enzymes still use which don't provide any hint as pepsin and trypsin

Systematic name The international union of Biochemistry and Molecular Biology (IUBMB) developed a system for nomenclature in which enzymes are divided into 6 groups and sub classes. These names are unambiguous and informative but sometimes long and difficult to be of general use. 1. 2. 3. Class Oxidoreductoases Transferases Hydrolases Reactions catalyzed oxidation-reduction transfer group of atoms hydrolysis

4.
5. 6.

Lyases
bond Isomerases Ligases

add/remove atoms to/from a double

rearrange atoms combine molecules using ATP

Enzyme Action: Lock and Key Model An enzyme binds a substrate in a region called the active site Active site is a special pocket or cleft in the enzyme molecule The active site contains amino acids side chains that form a three dimensional surface complementary to the substrate Only certain substrates can fit the active site The active site binds to the substrate and form enzyme-substrate complex that will dissociate into the enzyme and product. Amino acid R groups in the active site help substrate bind

Lock and Key

The active site of the unbound enzyme is complementary in shape to that of the substrate

Enzyme Action: Induced Fit Model

Enzyme structure flexible, not rigid Enzyme and active site adjust shape to bind substrate Increases range of substrate specificity Shape changes also improve catalysis during reaction

The enzyme changes shape upon binding substrate The active site has a shape complementary to that of the substrate only after the binding

Cofactors -Some enzymes associate with non-protein cofactor that is needed for enzymatic activity -These cofactor include metal ions (Zn, Fe) and organic molecules called coenzymes that often derivative of vitamins; NAD+, FAD, CoenzymeA.. -Holoenzyme refers to the enzyme with its cofactor, Apoenzyme refers to the protein portion of the holoenzyme and it dose not show biological activity. - Prosthetic group is a tightly bound enzyme that dose not dissociate from the enzyme Location of enzymes Many enzymes are located into specific organelles in the cell serve to isolate the

reaction substrate or product from each other

and to provide a special environment for a reaction and to organize these reactions

Nucleic Acids Nucleic acids are linear polymers of nucleotides-pyrimidine and purine bases linked to ribose or deoxyribose sugars (nucleosides) and bound to phosphate groups. The backbone of the nucleic acid consists of

alternating phosphate and pentose units with a purine or pyrimidine base

attached to each. The nucleotide has three characteristic components Nitrogenous base Pentose sugar Phosphate

DNA and RNA DNA differs from RNA in that it lacks a hydroxyl group at the pentose's C/ position, and it contains T rather than U. DNA structure consists of two a-helical DNA strands coiled around the same axis to form a double helix. The strands are antiparallel-the 5', 3'-internucleotide phosphodiester links run in opposite directions. RNA exists in three forms. (1) Ribosomal RNA (rRNA) functions as a framework to bind both messenger and transfer RNA. It is comprised of numerous subunits with the 405 and 605 being the most well known. Ribosomal RNA is also thought to have other functions; however, these have not been fully elucidated. (2) Messenger RNA (mRNA) serves as the template for protein synthesis and specifies a polypeptide's amino acid sequence. (3) Transfer RNA (tRNA) carries activated amino acids to the ribosomes, where the amino acids are incorporated into the growing polypeptide chain.

Nitrogenous Bases
Nitrogenous base: derivatives of Purines and pyrimidines DNA and RNA contain the same purine bases and the pyrimidine base Cytosine But Thymine found only in DNA and Uracil found only in RNA

(A)

(G)

(C)

(U)

(T)

Pentoses of Nucleotides
D-ribose (in RNA) 2-deoxy-D-ribose (in DNA) The difference - 2'-OH vs 2-H This difference affects secondary structure and stability

Nucleic Acids
Nucleic acid: are polymers of
Nucleotides linked with 3, 5- phosphodiester bonds Nucleotide residues are all oriented in the same direction (5 to 3) giving the polymer directionality.

5'

5'

3'

The sequence of DNA

molecules is always read in the 5 to 3 direction

3'

DNA
1o Structure - Linear array of nucleotides and their sequence can be determined by different methods. 2o Structure double helix 3o Structure - Super-coiling, stem-loop formation 4o Structure Packaging into chromatin

DNA Secondary structure

DNA is double stranded with antiparallel strands Right hand double helix Three different helical forms (A, B and Z DNA.

Bases from two adjacent DNA strands can hydrogen bond

Adenine pairs with thymine using two H-bonds

Guanine pairs with cytosine using three H-bonds

Properties of DNA Double Helix

* The two chains are coiled around a common axis * The chains are paired in an anti-parallel manner * Distance between the 2 sugar-phosphate backbones is always the same, give DNA

molecule a regular shape.

* Plane of bases are oriented perpendicular to backbone * Hydrophilic sugar phosphate backbone winds

around outside of helix

* Noncovalent interactions between upper and lower surfaces of base-pairs (stacking) forms a closely packed hydrophobic interior. * Hydrophobic environment makes H-bonding between bases stronger (no competition with water)

DNA 3o Structure
Supercoiling Cruciform structures DNA supercoiling:

Supercoiling: means the coiling

of the coil. Typical phone cord is coiled like

a DNA helix and the coiled cord

can itself coil in a supercoil A number of measurable

properties of supercoiling have

been established

DNA 4o Structure: Chromosome Structure

In chromosomes, DNA is tightly associated with proteins Human DNAs total length is ~2 meters! This must be packaged into a nucleus that is about 5 micrometers in diameter This represents a compression of more than 100,000! It is made possible by wrapping the DNA around protein spools called nucleosomes and then packing these in helical filaments

Nucleosome Structure
Chromatin, the nucleoprotein complex, consists of histones and nonhistone chromosomal proteins % major histone proteins: H1, H2A, H2B, H3 and H4 Histone octamers are major part of the protein spools Nonhistone proteins are regulators of gene expression

Nucleosome Structure
High content of Lysine and arginine (+ve charge) 4 major histone (H2A, H2B, H3, H4) proteins for octomer 200 base pair long DNA strand winds around the octomer 146 base pair DNA spacer separates individual nucleosomes H1 protein involved in higherorder chromatin structure. Chromatin looks like beads on string