8885dc05157-1898/12/038:55 AM Page158mac78mac78:385 158 Part I Structure and Catalysis excludes the binding of water, which may interact molecules illustrate almost every aspect of that most weakly and nonspecifically with many parts of central of biochemical processes: the reversible binding protein. In Chapter 6, we consider water as a of a ligand to a protein. This classic model of protein specific ligand for many enzymes. function tells us a great deal about how proteins work Proteins are flexible. Changes in conformation 6 Oxygen-Binding Proteins--Myoglobin: Oxygen Storage may be subtle, reflecting molecular vibrations and Oxygen Can Be Bound to a Heme Prosthetic Group small movements of amino acid residues throughout the protein. a protein flexing in this Oxygen is poorly soluble in aqueous solutions (see Table way is sometimes said to"breathe. Changes in 2-3)and cannot be carried to tissues in sufficient quan conformation may also be quite dramatic, with tity if it is simply dissolved in blood serum. Diffusion of major segments of the protein structure moving oxygen through tissues is also ineffective over distances as much as several nanometers. Specific greater than a few millimeters. The evolution of larger onformational changes are frequently essential to multicellular animals depended on the evolution of pro- a proteins function. teins that could transport and store oxygen. However, The binding of a protein and ligand is often none of the amino acid side chains in proteins is suited for the reversible binding of oxygen molecules. This role coupled to a conformational change in the protein is filled by certain transition metals, among them iron that makes the binding site more complementary to the ligand, permitting tighter binding. The and copper, that have a strong tendency to bind oxy gen. Multicellular organisms exploit the properties of structural adaptation that occurs between proten metals, most commonly iron, for oxygen transport. How and ligand is called induced fit. ever, free iron promotes the formation of highly reac In a multisubunit protein, a conformational tive oxygen species such as hydroxyl radicals that can change in one subunit often affects the damage DNA and other macromolecules. Iron used in conformation of other subunits cells is therefore bound in forms that sequester it and/or Interactions between ligands and proteins may be make it less reactive In multicellular organisms--espe- regulated, usually through specific interactions cially those in which iron, in its oxygen-carrying capac with one or more additional ligands. These other ty, must be transported over large distances--iron is of- igands may cause conformational changes in the ten incorporated into a protein-bound prosthetic group protein that affect the binding of the first ligand called heme.(Recall from Chapter 3 that a prosthetic group is a compound permanently associated with a pro- Enzymes represent a special case of protein func tein that contributes to the proteins function.) Heme (or haen) consists of a complex organic ring tion. Enzymes bind and chemically transform other mol- structure, protoporphyrin, to which is bound a single ecules--they catalyze reactions. The molecules acted upon by enzymes are called reaction substrates rather iron atom in its ferrous(Fe-s) state(Fig 5-1). The iron than ligands, and the ligand-binding site is called the atom has six coordination bonds, four to nitrogen atoms that are part of the flat porphyrin ring system and catalytic site or active site. In this chapter we two perpendicular to the porphyrin. The coordinated emphasize the noncatalytic functions of proteins. In Chapter 6 we consider catalysis by enzymes, a central nitrogen atoms(which have an electron-donating char topic in biochemistry. You will see that the themes of acter) help prevent conversion of the heme iron to the this chapter--binding, specificity, and conformational ferric(Fe t )state. Iron in the Fet state binds oxygen change-are continued in the next chapter, with the reversibly; in the Fe state it does not bind oxygen. added element of proteins acting as reactants in chem- Heme is found in a number of oxygen-transporting ical transformations proteins, as well as in some proteins, such as the cytochromes, that participate in oxidation-reduction (electron-transfer) reactions(Chapter 19) In free heme molecules (heme not bound to pro- 5.1 Reversible Binding of a Protein tein), reaction of oxygen at one of the two"open"CO- to a Ligand: Oxygen-Binding Proteins ordination bonds of iron(perpendicular to the plane of the porphyrin molecule, above and below) can result Myoglobin and hemoglobin may be the most-studied and in irreversible conversion of Fe-t to Fe. In heme- best-understood proteins. They were the first proteins containing proteins, this reaction is prevented by se- for which three-dimensional structures were deter- questering of the heme deep within the protein struc mined, and our current understanding of myoglobin and ture where access to the two open coordination bonds hemoglobin is garnered from the work of thousands of is restricted. One of these two coordination bonds is oc- biochemists over several decades. Most important, these cupid by a side-chain nitrogen of a His residue. Theexcludes the binding of water, which may interact weakly and nonspecifically with many parts of a protein. In Chapter 6, we consider water as a specific ligand for many enzymes.) Proteins are flexible. Changes in conformation may be subtle, reflecting molecular vibrations and small movements of amino acid residues throughout the protein. A protein flexing in this way is sometimes said to “breathe.” Changes in conformation may also be quite dramatic, with major segments of the protein structure moving as much as several nanometers. Specific conformational changes are frequently essential to a protein’s function. The binding of a protein and ligand is often coupled to a conformational change in the protein that makes the binding site more complementary to the ligand, permitting tighter binding. The structural adaptation that occurs between protein and ligand is called induced fit. In a multisubunit protein, a conformational change in one subunit often affects the conformation of other subunits. Interactions between ligands and proteins may be regulated, usually through specific interactions with one or more additional ligands. These other ligands may cause conformational changes in the protein that affect the binding of the first ligand. Enzymes represent a special case of protein func￾tion. Enzymes bind and chemically transform other mol￾ecules—they catalyze reactions. The molecules acted upon by enzymes are called reaction substrates rather than ligands, and the ligand-binding site is called the catalytic site or active site. In this chapter we emphasize the noncatalytic functions of proteins. In Chapter 6 we consider catalysis by enzymes, a central topic in biochemistry. You will see that the themes of this chapter—binding, specificity, and conformational change—are continued in the next chapter, with the added element of proteins acting as reactants in chem￾ical transformations. 5.1 Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins Myoglobin and hemoglobin may be the most-studied and best-understood proteins. They were the first proteins for which three-dimensional structures were deter￾mined, and our current understanding of myoglobin and hemoglobin is garnered from the work of thousands of biochemists over several decades. Most important, these molecules illustrate almost every aspect of that most central of biochemical processes: the reversible binding of a ligand to a protein. This classic model of protein function tells us a great deal about how proteins work. Oxygen-Binding Proteins—Myoglobin: Oxygen Storage Oxygen Can Be Bound to a Heme Prosthetic Group Oxygen is poorly soluble in aqueous solutions (see Table 2–3) and cannot be carried to tissues in sufficient quan￾tity if it is simply dissolved in blood serum. Diffusion of oxygen through tissues is also ineffective over distances greater than a few millimeters. The evolution of larger, multicellular animals depended on the evolution of pro￾teins that could transport and store oxygen. However, none of the amino acid side chains in proteins is suited for the reversible binding of oxygen molecules. This role is filled by certain transition metals, among them iron and copper, that have a strong tendency to bind oxy￾gen. Multicellular organisms exploit the properties of metals, most commonly iron, for oxygen transport. How￾ever, free iron promotes the formation of highly reac￾tive oxygen species such as hydroxyl radicals that can damage DNA and other macromolecules. Iron used in cells is therefore bound in forms that sequester it and/or make it less reactive. In multicellular organisms—espe￾cially those in which iron, in its oxygen-carrying capac￾ity, must be transported over large distances—iron is of￾ten incorporated into a protein-bound prosthetic group called heme. (Recall from Chapter 3 that a prosthetic group is a compound permanently associated with a pro￾tein that contributes to the protein’s function.) Heme (or haem) consists of a complex organic ring structure, protoporphyrin, to which is bound a single iron atom in its ferrous (Fe2
) state (Fig. 5–1). The iron atom has six coordination bonds, four to nitrogen atoms that are part of the flat porphyrin ring system and two perpendicular to the porphyrin. The coordinated nitrogen atoms (which have an electron-donating char￾acter) help prevent conversion of the heme iron to the ferric (Fe3
) state. Iron in the Fe2
state binds oxygen reversibly; in the Fe3
state it does not bind oxygen. Heme is found in a number of oxygen-transporting proteins, as well as in some proteins, such as the cytochromes, that participate in oxidation-reduction (electron-transfer) reactions (Chapter 19). In free heme molecules (heme not bound to pro￾tein), reaction of oxygen at one of the two “open” co￾ordination bonds of iron (perpendicular to the plane of the porphyrin molecule, above and below) can result in irreversible conversion of Fe2
to Fe3
. In heme￾containing proteins, this reaction is prevented by se￾questering of the heme deep within the protein struc￾ture where access to the two open coordination bonds is restricted. One of these two coordination bonds is oc￾cupied by a side-chain nitrogen of a His residue. The 158 Part I Structure and Catalysis 8885d_c05_157-189 8/12/03 8:55 AM Page 158 mac78 mac78:385_REB: