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

2. 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

3. Biochemistry & nutrition
Table 24-2, p.666

4. 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

5. 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 Copyright © 2002 Nature. Reprinted with permission.)

6. FIGURE 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 )

7. 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

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

10. Organ specialization

11. Brain

12. Muscle

13. Liver

14. 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)

15. 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

16. 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

20. 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

21. 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.

22. Table 24-3, p.672

23. 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

24. 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

25. Second messenger e.g cyclic AMP (cAMP)

26. 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

27. 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

28. 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

29. FIGURE 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 , p.682

30. 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 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.

31. Metabolic homeostasis

33. FIGURE 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.

34. Table 24-4, p.685

40. 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.