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Week Three Lecture 560B on Line

Week Three Lecture 560B on Line

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Week Three LectureBiochemistry of Nutrition, 560BDr. Charles SaladinoIntroduction
I think it is safe to say that in terms of functionality, proteins represent the most diverse group of  biomolecules encountered in living systems. Let us consider this point:1. Although not the main source of nutrition in most “American diets” (whatever that is), proteins canact as a major fuel source.2. Almost all enzymes are proteins. (Notice I said “almost,” because there are some ribosomal-associated RNA species that have enzymatic activity.) Simply put, without this class of proteins calledenzymes, metabolism would proceed too slowly to be compatible with life.3. There are numerous groups of proteins that are functionally designed for structural purposes. Thesewould include the collagens (seen in bones, ligaments and tendons, for example), elastins of the skinand arterial walls, and reticular connective tissue components. However, let us not neglect to remindourselves that integral proteins of a structural nature are also found within membranes, thecytosketeton, microtubules, etc.4. Antibodies are proteins.5. There are a large number of coagulation cascade proteins.6. Storage proteins play an important role in sequestering important ions. For example, ferritin isinvolved in iron storage, whereas calmodulin is a calcium-binding protein that is important inmetabolic regulation.7. Genetic regulatory proteins are critical to controlling the appropriate expression of gene activity or inactivity.8. Transport proteins, often integrated into membranes, are important in carrying various substances inand out of cells in a regulated manner. A good example is the glucose transporter. On a grander scale,however, there is albumin, designed to bind to a variety of plasma substances.9. Proteins, such as myosin and actin, are key components of cardiac and skeletal myocytes and are inlarge part responsible for the contractile properties such cells.10. Heat shock proteins can be subdivided into groups of proteins that not only escort proteins from onearea of a cell to another site within that same cell (thus acting as transporters), but they also function to protect the three-dimensional structure of enzymes and other proteins in times of metabolic stress.Such stress conditions include aberrant changes in temperature, pH, and oxygen tension.11. There are a variety of hormones which are protein in nature. These include the well known insulinmolecule, glucagon, and a variety of neuropeptides. Other proteins that serve as an example of regulatory proteins at the cellular/tissue level would be angiotensin, involved directly in
vasoconstriction and indirectly in cardiohypertrophy.12. Finally, many proteins are conjugated to other biomolecules. These would include lipids to formlipoproteins and various carbohydrate moieties to form glycoproteins (as seen in cell membranereceptors) and various mucopolysaccharides, for example. Also, there are metalloproteins, obviouslynamed, such as the Fe-S cluster proteins of the detoxification system and located in the inner mitochondrial membranes in the hepatocytes. In addition, there are hene proteins, such as the well-described myoglobin and hemoglobin molecules.From this list of functions, each but briefly described, it is quite evident that as a class of biomolecules, proteins constitute a large spectrum of functions. In addition, and of real importance, is the fact thatonly proteins can effectively carry out many of these functional duties, due to the absolute requirementfor the great specificity that lies within their respective highly-specific, three-dimensionalconfigurations. For example, the effectiveness of antibodies to neutralize precise foreign moleculesand agents requires great specificity against its antigen.. The importance of this is seen inautoimmunity, wherein this specificity is lost. The same need for specificity applies to the action of enzymes upon specific substrates and peptide hormones acting as ligands to their respective receptors.In order to appreciate this specificity of action of various proteins, it is critical that we not onlyunderstand their respective three-dimensional structures, but we must also appreciate those factors thatdetermine precisely what geometric configurations a particular protein will assume. Besides a host of other factors, such as hydration, energy levels, etc., what we learned last week about pK 
will nowassume a major role in what the final 3-D array of the protein will in fact be.
Protein Structure
I understand that making the statement that proteins are comprised of amino acids is doctrinaire to you.So let us start to discuss the various levels of protein structure, which will ultimately determine thefunctionality of a given protein.The
structure of a protein is the specific amino acid sequence that comprises that protein; andthis primary structure will ultimately be the major determinant of all higher order structure or folding of that protein. In order for a primary structure to be realized, each amino acid must be bonded to anadjacent amino acid through the formation of a strong peptide bond, which in organic chemistry, wewould call an amide bond. I refer you to
Figure 3.24 in Devlin.
Please notice that the amine group of one amino acid is covalently bonded to the carbonyl carbon (the one with the double-bonded oxygen)of the adjacent amino acid. This peptide bond – again an amide bond – results from the reaction process known as a dehydration synthesis – pretty self explanatory. The oxygen from one amino acid’scarboxyl group and two hydrogen atoms from the amine group (ammonium ion) of the other aminoacid are removed enzymatically (in total constituting a dehydration reaction), allowing the formation of a bond between the nitrogen of one amino acid and the carbonyl carbon. of another amino acid. Notice carefully that this peptide bond formation does not involve any part of the R side chain group.Such interactions are for later consideration.If you see the term, dipeptide, this refers to two amino acids joined together by one peptide bond.Thus, a tripeptide is three amino acids (joined by two peptide bonds). Further, if you should see anamino acid sequence, such as Tyr-Phe-Gly-Gly-Leu, the tyrosine is the N-terminal amino acid (i.e.starting with an amine), whereas the leucine is the C-terminal amino acid (i,e. ending in a carboxyl).
 Now folks, if we look at the same Figure 3.24 in Devlin, we note that the peptide bond itself is rigid.That is, it does not rotate, any more than the double or triple bond between two carbons can rotate.H
owever, if you look carefully at the figure, there are respective and bonds on either side of the
 peptide bond. These can and in fact do rotate.
So why am I making a point about this?Well, these rotations allow configuration (3-D) changes in the way a polypeptide chain can in factconfigure. It also causes some 3-D or conformational constraints, known as steric hindrance, when, for example, two hydrogens are rotated too close to one another. Their respective electrons will repel.What does all this boil down to? Well, it provides for many permutations/combinations of where the R groups of each amino acid will be positioned with respect to one another. This, in turn, will affect possible interactions between R groups, which in turn exert a tremendous affect upon higher order  protein structure and thus its function. (Remember lecture one, structure/function relationships????)Before we investigate how interactions between amino acids (known also as amino acid residues) of a polypeptide determine the protein’s three-dimensional structure, (as well as its functional role andrelationship to other proteins), let us define polypeptides that have similar amino acid sequences andfunctions as
This is significant, because sequence comparisons among homologous polypeptides have been used to evaluate genetic relationships of different species. For example, acomparison of the mitochondrial oxidation/reduction protein, cytochrome C, among different speciesreveals a significant amount of sequence conservation. Further, those amino acids within a given protein which do not differ from species to species are referred to as invariant and are believed to beessential for the function of that protein. This is why, for example, there are invariant similarities andsome variant differences in the structure of human vs. that of porcine vs. that bovine insulin. It is theseinvariant amino acids that allow porcine insulin to be substituted for that of human insulin in somecases. I wouldn’t be surprised if the variant differences, however, could contribute to immunologicalreactions by a human against say porcine insulin. Thus, the use of genetically-engineered humaninsulin produced from bacteria.There are many other examples. Later, when we study energy transformation in the mitochondria, weshall see that the invariant amino acid residues in cytochrome C are essential for interaction with theimportant heme group.One other point: Some amino acid substitutions do not affect the function of the protein. They arereferred to as conservative substitutions, whereas those amino acid substitutions which result in adefective protein are known as non-conservative substitutions. Now we can state the bottom line of primary structure. It is whatever amino acids are bonded together via peptide bonds in whatever order they appear. This primary amino acid sequence forms the basis for all higher order protein structure – various types of folding through bonding interactions.When we consider the
structure of a protein, we need to realize that a polypeptide chainconsists of a regularly repeating structure, called the backbone, and a variable component comprisingdistinct R side chains of their respective amino acids. The polypeptide is very rich in potentialhydrogen bonds, because each amino acid residue contains a carbonyl group (a good hydrogen bondacceptor – except for proline) and an amine group (a good hydrogen bond donor). This is the basis of secondary structure, which assumes one of two likely configurations. The first is the alpha
α(right-handed) helix, and second is the beta-pleated sheet. Your text shows the
α in
Figures 3.25 and

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