Metabolic interrelationship Chapter 6: Integration, Specialization, and Regulation of Metabolism

At this point, we’ll consider how organisms arrange/organize the metabolic symphony to meet their energy needs. Discussion will include how: Body maintains energy balance (homeostasis) It deals with starvation It responds to the loss of control from diabetes mellitus

Biochemistry & nutrition Table 24-2, p.666

Food pyramid FIGURE 24.2 The Food Guide Pyramid (USDA). The recommended choices reflect a diet based primarily on carbohydrates. Smaller amounts of proteins and lipids are sufficient to meet the body’s needs. Fig. 24-2, p.668

Has been established in mice Obesity Has been established in mice in mice, leptin is 16kDa protein that produced by obesity (ob) gene mutation in this gene will lead to deficiency of leptin Define as weighing at least 20% more than their ideal weight several inventions: artificial sweeteners, fat substitutes protein leptin plays a role in the control of obesity FIGURE 24.4 Leptin has multiple effects on metabolism. It affects the brain, lowering appetite. It also inactivates acetyl-CoA carboxylase (ACC). Reduced activity of ACC leads to a reduction in malonyl- CoA, which stimulates fatty-acid oxidation and reduces fatty-acid synthesis. (From Nature, Vol. 415 (January 17, 2002), Fig 1, p. 268. Copyright © 2002 Nature. Reprinted with permission.)

FIGURE 19.15 A summary of anabolism, showing the central role of the citric acid cycle. Note that there are pathways for the biosynthesis of carbohydrates, lipids, and amino acids. OAA is oxaloacetate, and ALA is -aminolevulinic acid. Symbols are as in Figure 19.10.)

Review of metabolism Glycolysis Gluconeogenesis The pentose phosphate pathway Β oxidation and fatty acids synthesis Amino acids degradation and synthesis The citric acid cycle Oxidative phosphorylation

Intermediates that connect pathways Glucose-6-phosphate Pyruvate Acetyl-CoA Oxaloacetate Intermediates that connect pathways

Organ specialization

Brain

Muscle

Liver

The fate of G6P varies with metabolic requirements – depends on the glucose demand G6P can be converted to glucose by glucose-6-phosphatase (transport via bloodstream to the peripheral organs) G6P can be converted to glycogen – when body’s demand for glucose is low G6P can be converted to acetyl-CoA via glycolysis and action of pyruvate dehydrogenase (this glucose-derived acetyl-CoA used in the synthesis of f.acids) G6P can be degraded via pentose phosphate pathway (to generate NADPH required for f.acids biosynthesis and liver’s many other biosynthetic functions)

The liver can synthesize or degrade TAGs When metabolic fuel is needed, f.acids are degraded to acetyl-CoA and then to ketone bodies (export via bloodstream to the peripheral tissues) When the demand is low, f.acids are used to synthesize TAGs (secreted into the bloodstream as VLDL for uptake by adipose tissue) Amino acids are important metabolic fuel The liver degrades amino acids to a variety of intermediates (begin with a.acid transamination to yield α-keto acid, via urea cycle excreted urea) Glucogenic a.acid – converted to pyruvate / OAA (TCA cycle intermediates) Ketogenic a.acid – converted to ketone bodies

Kidney Overall reaction in kidney: Glutamine → α-ketoglutarate + NH4+ During starvation, the α-ketoglutarate enters gluconeogenesis (kidneys generate as much as 50% of the body’s glucose supply) α-ketoglutarate : converted to malate (TCA cycle) : pyruvate (oxidized to CO2) or via OAA to PEP : converted to glucose via gluconeogenesis Functions : to filter out the waste product urea from the bloodstream : to concentrate it for excretion : to recover important metabolites (glucose) : to maintain the blood pH

Hormones and second messengers FIGURE 24.5 Endocrine cells secrete hormones into the bloodstream, which transports them to target cells. Hormones reacts as the intercellular messengers Hormones transported from the sites of their synthesis to the sites of action by the bloodstream Fig. 24-5, p.671

Some typical hormones: - steroids (estrogens, androgens) - polypeptides (insulin and endorphins) - a.acid derivatives (epinephrine and norepinephrine) Hormones help maintaining homeostasis (the balance of biological activities FIGURE 24.6 A simple feedback control system involving an endocrine gland and a target organ.

Table 24-3, p.672

Control system mechanism Hormone releasing factor FIGURE 24.7 Hormonal control system showing the role of the hypothalamus, pituitary, and target tissues. See Table 24.3 for the names of the hormones. Fig. 24-7, p.673

FIGURE 24.8 Nonsteroid hormones bind exclusively to plasmamembrane receptors, which mediate the cellular responses to the hormone. Steroid hormones exert their effects either by binding to plasma-membrane receptors or by diffusing to the nucleus, where they modulate transcriptional events. Fig. 24-8, p.674

Second messenger e.g cyclic AMP (cAMP)

FIGURE 24.9 Activation of adenylate cyclase by heterotrimeric G proteins. Binding of hormone to its receptor causes a conformational change that induces the receptor to catalyze a replacement of GDP by GTP on G. The G (GTP) complex dissociates from G and binds to adenylate cyclase, stimulating synthesis of cAMP. Bound GTP is slowly hydrolyzed to GDP by the intrinsic GTPase activity of G. G (GDP) dissociates from adenylate cyclase and reassociates with G. G and G are lipidanchored proteins. Adenylate cyclase is an integral membrane protein consisting of 12 transmembrane -helical segments. Fig. 24-9a, p.675

FIGURE 24.9 Activation of adenylate cyclase by heterotrimeric G proteins. Binding of hormone to its receptor causes a conformational change that induces the receptor to catalyze a replacement of GDP by GTP on G. The G (GTP) complex dissociates from G and binds to adenylate cyclase, stimulating synthesis of cAMP. Bound GTP is slowly hydrolyzed to GDP by the intrinsic GTPase activity of G. G (GDP) dissociates from adenylate cyclase and reassociates with G. G and G are lipidanchored proteins. Adenylate cyclase is an integral membrane protein consisting of 12 transmembrane -helical segments. Fig. 24-9b, p.675

Hormones & metabolism The effects of hormones triggered the responses within the cell There are three hormones play a part in the regulation of CHO metabolism Epinephrine, insulin and glucagon Epinephrine: acts on muscle tissue, to raise level of glucose on demand, when it binds to specific receptors, it leads to increased level of glucose in blood, increased glycolysis in muscle cells and increased breakdown of f.acid for energy Tyrosine and epinephrine. The hormone epinephrine is metabolically derived from the amino acid tyrosine. p.681

FIGURE 24.14 When epinephrine binds to its receptor, the binding activates a stimulatory G protein, which in turn activates adenylate cyclase. The cAMP thus produced activates a cAMPdependent protein kinase. The phosphorylation reactions catalyzed by the cAMP-dependent kinase suppress the activity of glycogen synthase and enhance that of phosphorylase kinase. Glycogen phosphorylase is activated by phosphorylase kinase, leading to glycogen breakdown. Fig. 24-14, p.682

Glucagon: acts on liver, to increase the availability of glucose, when it binds to specific receptors, it leads to increased level of glucose in blood. FIGURE 24.15 Binding of glucagon to its receptor sets off the chain of events that leads to the activation of a cAMP-dependent protein kinase. The enzymes phosphorylated in this case are phosphofructokinase-2, which is inactivated, and fructose-bisphosphatase-2, which is activated. The combined result of phosphorylating these two enzymes is to lower the concentration of fructose-2,6-bisphosphate (F2,6P). A lower concentration of F2,6P leads to allosteric activation of the enzyme fructose-bisphosphatase, thus enhancing gluconeogenesis. At the same time, the lower concentration of F2,6P implies that phosphofructokinase is lacking a potent allosteric activator, with the result that glycolysis is suppressed.

Metabolic homeostasis

FIGURE 24.16 Proinsulin is an 86-residue precursor to insulin (the sequence shown here is human proinsulin). Proteolytic removal of residues 31 through 65 yields insulin. Residues 1 through 30 (the B chain) remain linked to residues 66 through 86 by a pair of interchain disulfide bridges.

Table 24-4, p.685

Metabolic adaptation During prolonged starvation or fasting, the brain slowly adapts from the use of glucose as its soul fuel source to the use of ketone bodies, shift the metabolic burden form protein breakdown to fat breakdown Diabetes mellitus is a disease in which insulin either not secreted or doesn’t stimulate its target tissues → high [glucose] in the blood and urine. Abnormally high production of ketone bodies is one of the most dangerous effects of uncontrolled diabetes Dieting – to lose excess weight. Diet forced the body to follow the same adjustment like starvation or fasting but a more moderate or controllable pace. Dieting is not free of problems, therefore it is advisable to undergo diet under supervision of physician or nutritionist.