PDQ BIOCHEMISTRY - PART 2 pptx

from ATP by the enzyme adenylate cyclase. cAMP is the second messenger, and it triggers a sequence of biochemical events within the cell that leads to a definite physiologic response. This situation may be compared to your reaction to a friend who tele- phones you in your hotel room to wake you in the morning. (Picture your- self in some luxurious Hilton Hotel in Cancun, if you will.) The telephone call triggers a series of responses from you (rising, showering, dressing, eat- ing, leaving for a day’s trip to the Mayan pyramids) that would possibly not happen should your friend forget to call you. The telephone call is like the second messenger (cAMP) that is initiated within your room by your friend’s action from the outside. cAMP was discovered in the 1950s by Earl Sutherland, who won the Nobel Prize for this novel finding of a second messenger. The generation of cAMP within the smooth muscle cell following adrenergic stimulation leads to the activation of an enzyme called protein kinase A (PKA) (see Fig- 28 PDQ BIOCHEMISTRY Calmodulin Falling Ca 2+ Rising Ca 2+ Calmodulin Ca 2+ MLCK ADP ATP Phosphatase Myosin Light Chain (This allows myosin–actin interaction) P + Myosin Light Chain (This inhibits myosin–actin interaction) - P Figure 1–16 Mechanism of smooth muscle contraction. When levels of free Ca ++ increase within smooth muscle cells, Ca ++ –calmodulin complexes are formed that activate myosin light chain kinase (MLCK). The phosphorylation of the myosin light chain facilitates the interaction of myosin and actin, and muscle contraction is promoted. With falling levels of free Ca ++ , the MLCK activity declines and myosin light chains can be dephosphorylated by a phosphatase. Myosin light chains once again block myosin–actin interaction, and muscle relaxation is pro- moted. mechanism involves a gas, made within your body, and whose absence fig- ures largely in what is coyly referred to as ED (erectile dysfunction). NITRIC OXIDE If you have a parent or grandparent with a heart condition, you may be aware that these patients are often prescribed nitroglycerine pills. These are generally taken for the onset of angina, pain caused by insufficient blood flow to the heart. The use of nitroglycerine pills leads to vasodilation and is of particular importance at the coronary arteries. Nitroglycerine can serve as a source of nitrate for your cells, and certain of these can generate nitric oxide (NO) from the conversion of nitrate to nitrite and nitrite to NO (Figure 1–19). As it is a gas, NO can travel into cells and does not make use of a receptor at the cell surface. NO acts as a vasodila- tor that is involved in the control of blood pressure. Initially,it was observed that acetylcholine acted as a vasodilator in blood vessels. However,when this effect was studied further, it was noted that the effect of acetylcholine was not exerted directly on the smooth muscle of the vessel itself. When endothe- lial cells of the vessel were removed from the smooth muscle, there was no direct vasodilatory effect of acetylcholine. It appears that acetylcholine, interacting with its receptor on endothelial cells, triggers a rise in intracel- lular calcium and a formation of NO in the cytoplasm of the endothelial cell from the amino acid arginine, by the action of the enzyme NO synthase (NOS) (see Figure 1–19). NO diffuses from the endothelial cell and enters the underlying smooth muscle cells, where it stimulates the production of cyclic GMP (cGMP, a compound similar in structure to cAMP). cGMP 30 PDQ BIOCHEMISTRY Caldesmon- Caldesmon-Ca 2+ -Calmodulin Caldesmon-Tropomyosin-Actin ATP (Allows actin–myosin interaction) Rising Ca 2+ Ca 2+ -Calmodulin Falling Ca 2+ (Blocks actin–myosin interaction) P (Allows actin–myosin interaction) P Figure 1–18 Role of caldesmon in smooth muscle contraction. Caldesmon is a protein that binds to tropomyosin and actin and prevents myosin–actin interaction. With rising levels of Ca 2+ , Ca 2+ -calmodulin binds to caldesmon, permitting access of actin to myosin and muscle contrac- tion. A similar result follows the phosphorylation of caldesmon, as the phosphorylated protein does not bind actin. A phosphatase returns caldesmon to its original conformation, permitting interaction with tropomyosin–actin. ation of ATP, glucose or another fuel enters the cells from the blood and is broken down. The energy that is released is conserved, in part, by the for- mation of ATP. The breakdown of glucose initially involves a process called glycolysis (meaning splitting of sugar), which we shall deal with in more detail in Chapter 7. Muscle cells also have supplies of glycogen, a polymer of glucose, that can be broken down to supply the compound glucose-6- phosphate for glycolysis (Figure 1–20). Glycolysis supplies some ATP for cells, and the end product of glycoly- sis (pyruvate) can enter into mitochondria and be further broken down, supplying energy for a process called oxidative phosphorylation. In this process, considerable ATP is made and travels back into the cellular cyto- plasm. This ATP, in turn, can serve as a substrate for the enzyme creatine kinase, which phosphorylates a compound called creatine. Creatine phos- phate represents a stored form of chemical energy within cells. In times of need, creatine phosphate is used in the formation of ATP from ADP by cre- atine kinase, and the ATP is used in muscle contraction. In turn, the ADP generated during contraction is recycled back to ATP in the mitochondria by ongoing oxidative phosphorylation. We shall consider these processes in more detail in Chapter 7, but it is important that you have an overview of how energy is supplied for ATP synthesis and how ATP serves as a carrier of chemical energy between the mitochondria or creatine phosphate stores and the muscle filaments, which are the sites of muscle contraction. 32 PDQ BIOCHEMISTRY Glycogen Glucose-6-PGlucose Glycolysis Pyruvate CO 2 , H 2 O ATP Krebs Cycle Oxidative Phosphorylation ADP Creatine Phosphate Creatine ATP Creatine Kinase ADP Figure 1–20 Muscle contraction and the supply of energy. Muscle glycogen and glucose can provide substrates for glycolysis. Glycolysis and the Krebs cycle (via oxidative phosphorylation) provide ATP that can be used in muscle contraction or in the formation of creatine phosphate. The latter acts as an energy store that can be used to reclaim ATP. This chapter has provided an introduction to proteins and many of the functions associated with these dynamic molecules. Table 1–1 summarizes the functions of the proteins that we have discussed here and some exam- ples of each. Some proteins can play multiple roles. The ryanodine recep- tor is considered a receptor because it can bind calcium, but it is also a lig- and-gated channel for calcium ions coming from the sarcoplasmic reticulum into the cytoplasm of the muscle cell. Similarly, the acetylcholine receptor binds acetylcholine and also functions as a ligand-gated channel. Na + ,K + -ATPase certainly has enzyme properties but also facilitates active transport. These multiple roles of proteins emphasize that proteins may have different regions or domains that can carry out distinct functions. Pro- teins that carry out these various functions will be the prominent features of this book and will appear in each of the subsequent chapters. Chapter 1 Proteins: Introduction to Proteins and the Biochemistry of Muscle 33 Table 1–1 Functions of Proteins Function Examples of Proteins Contraction and regulation Actin, myosin, tropomyosin, troponins, of contraction calmodulin, caldesmon Structural Collagen, α-keratin Enzymes (catalysis of Myosin ATPase, myosin light chain kinase, reactions) phosphatase, acetylcholinesterase, nitric oxide synthase (NOS), protein kinase A (PKA), cGMP- activated protein kinases, Na + , K + -ATPase Receptors (at plasma Acetylcholine receptor, α- and β-adrenergic receptors membrane) (for adrenalin) Receptors (T-tubule and Dihydropyridine receptor (DHPR), ryanodine intracellular) receptor (RyR) Channels: Voltage-gated Dihydropyridine receptor, Na + -channel Ligand-gated Acetylcholine receptor, ryanodine receptor Transporters (membrane Na + , K + -ATPase, Na + -Ca ++ exchanger, Na + -H + bound, at plasma exchanger membrane) Transporters (intracellular) Ca 2+ -ATPase ATP = adenosine triphosphate; cGMP = cyclic guanosine monophosphate. [...]... cannot simply unload triglycerides into cells Rather, the lipoproteins are actually broken 62 PDQ BIOCHEMISTRY Table 2 4 Characteristics of Lipoproteins Chylomicrons VLDLs LDLs Density (g/mL) . cAMP). cGMP 30 PDQ BIOCHEMISTRY Caldesmon- Caldesmon-Ca 2+ -Calmodulin Caldesmon-Tropomyosin-Actin ATP (Allows actin–myosin interaction) Rising Ca 2+ Ca 2+ -Calmodulin Falling Ca 2+ (Blocks actin–myosin. activation of an enzyme called protein kinase A (PKA) (see Fig- 28 PDQ BIOCHEMISTRY Calmodulin Falling Ca 2+ Rising Ca 2+ Calmodulin Ca 2+ MLCK ADP ATP Phosphatase Myosin Light Chain (This allows. muscle filaments, which are the sites of muscle contraction. 32 PDQ BIOCHEMISTRY Glycogen Glucose-6-PGlucose Glycolysis Pyruvate CO 2 , H 2 O ATP Krebs Cycle Oxidative Phosphorylation ADP Creatine