Chapter 9 Metabolic Integration and Organ Specialization

“Study of an enzyme, a reaction, or a sequence can be biologically relevant only if its position in the hierarchy of function is kept in mind.” Daniel E. Atkinson Seoul Metro Map, a metaphor for metabolic function.

Catabolic and anabolic pathways, occurring simultaneously, must act as a regulated and orderly manner.

ATP Coupling Determines the Keq for Metabolic Sequences The overall thermodynamic efficiency of any metabolic sequence is determined by ATP coupling. The overall reaction mediated by any pathway is energetically favored because of its particular ATP produce/consume ratio. The involvement of ATP alters the free energy change for a reaction. Put another way, the role of ATP is to change the equilibrium ratio of [reactants] to [products] for a reaction.

The Significance of 38 ATPs Consider glucose oxidation If 38 ATP are produced, cellular G is -967 kJ/mol and Keq = 10170, a very large number! This ensures that glucose oxidation will go to completion. More ATP could be produced, but glucose oxidation would be incomplete. The number of 38 is an end result of biological adaptation. This adaptation provides a high yield of ATP for each glucose.

The roles of ATP in metabolism ATP serves as the energy currency of the cell. It also helps in establishment of large equilibrium constants for metabolic conversions and to give metabolic reactions sequences thermodynamically favorable. ATP also serves as an important allosteric effector in the kinetic regulation of metabolism. ATP concentration is an index of the energy status of the cell and determines the rates of regulatory enzymes situated at key points in metabolism.

Is There a Good Index of Cellular Energy Status? Energy transduction and energy storage in the adenylate system – ATP, ADP, and AMP – is the core of metabolism. The regulation of metabolism by adenylates in turn requires tight control of the relative concentrations of ATP, ADP, and AMP. Adenylate kinase provides a direct connection among all three members of the adenylate pool. Adenylates provide phosphoryl groups to drive thermodynamically unfavorable reactions. Energy charge is an index of how fully charged adenylates are with phosphoric anhydrides. If [ATP] is high, energy charge approaches 1.0 If [ATP] is low, energy charge approaches 0

How is Overall Energy Balance Regulated in Cells? AMP-activated protein kinase (AMPK) is the cellular energy sensor. Metabolic inputs to this sensor determine whether its output (protein kinase activity) takes place. When ATP is high, AMPK is inactive. When ATP is low, AMPK is allosterically activated and phosphorylates many targets controlling cellular energy production and consumption. AMPK is an αβγ heterotrimer; the α-subunit is the catalytic subunit and the γ-subunit is regulatory. The β-subunit has an αγ-binding domain that brings α and γ together.

AMPK regulation of energy production and consumption in mammals.

How Is Metabolism Integrated in a Multicellular Organism? Organ systems in complex multicellular organisms have arisen to carry out specific functions. Such specialization depends on coordination of metabolic responsibilities among organs so that the organism as a whole can survive. Organs differ in the metabolic fuels they prefer as substrates for energy production. The major fuel depots in animals are glycogen in live and muscle; triacylglycerols in adipose tissue; and protein, mostly in skeletal muscle. The usual order of preference for use of these is glycogen > triacylglycerol > protein.

How Is Metabolism Integrated in a Multicellular Organism?

The Brain Has a High Metabolism and Normally Uses Only Glucose as a Fuel The brain has very high metabolism but has no fuel reserves. This means the brain needs a constant supply of glucose. In fasting conditions, the brain can use -hydroxybutyrate (from fatty acids), converting it to acetyl-CoA in the TCA cycle. This allows the brain to use fat as fuel.

Ketone bodies such as β-hydroxybutyrate provide the brain with a source of acetyl-CoA when glucose is unavailable.

Creatine Kinase and Phosphocreatine Provide an Energy Reserve in Muscle Muscles must be prepared for rapid provision of energy. Creatine kinase and phosphocreatine act as a buffer system, providing additional ATP for contraction. Glycogen provides additional energy, releasing glucose for glycolysis. Glycolysis is capable of explosive bursts of activity. The flux of glucose-6-P through glycolysis can increase 2000-fold almost instantaneously. Glycolysis rapidly lowers pH, causing muscle fatigue.

Athletic Performance Enhancement with Creatine Supplements? The creatine pool in a 70 kg (154 lb) human body is about 120 grams Of this creatine, 95% is stored in the skeletal and smooth muscles, about 70% of which is in the form of phosphocreatine Supplementing the diet with 20 to 30 grams of creatine per day for 4 to 21 days can increase the muscle creatine pool by as much as 50% Studies show that such supplementation can improve athletic performance in high-intensity, short-duration events. The FDA advises consumers to consult a physician before using creatine as a supplement.

Athletic Performance Enhancement with Creatine Supplements? Creatine supplements may enhance performance for high-intensity, short-duration events such as weight-lifting.

The Liver is the Major Metabolic Processing Center in Vertebrates Most of the incoming nutrients that pass through the intestines are routed via the portal vein to the liver for processing and distribution Liver activity centers around glucose-6-phosphate Glucose-6-phosphate can be: converted to glycogen released as blood glucose, used to generate NADPH and pentoses via the pentose phosphate pathway, or catabolized to acetyl-CoA for fatty acid synthesis or for energy production in oxidative phosphorylation

Metabolic conversions of glucose-6-phosphate in the liver.

What Regulates Our Eating Behavior? Approximately two-thirds of American are overweight One-third of Americans are clinically obese Obesity is the most important cause of type 2 diabetes Research into the regulatory controls on feeding behavior has become a medical urgency The hormones that control eating behavior come from many different tissues Hormones that regulate eating include: Short-term regulators determine individual meals Long-term regulators stabilize levels of body fat deposits

Can You Really Live Longer by Eating Less? Caloric restriction leads to longevity. For most organisms, caloric restriction results in lower blood glucose levels, declines in glycogen and fat stores, enhanced responsiveness to insulin, lower body temperature, and diminished reproductive capacity. Caloric restriction also reduces the likelihood for development of many age-related diseases, including cancer, diabetes, and atherosclerosis.

Mutations in the SIR2 Gene Decrease Life Span Deletion of a gene termed SIR2 abolishes the ability of caloric restriction to lengthen life in yeast and roundworms This implicates the SIR2 gene product in longevity The human gene analogous to SIR2 is SIRT1, for sirtuin 1 Sirtuins are NAD+-dependent protein deacetylases The tissue NAD+/NADH ratio controls sirtuin protein deacetylase activity Oxidative metabolism, which drives conversion of NADH to NAD+, enhances sirtuin activity

Resveratrol in Red Wine is a Potent Activator of Sirtuin Activity French people enjoy longevity despite a high-fat diet. Resveratrol may be the basis of this “French paradox”. Resveratrol, a phytoalexin, is a member of the polyphenol class of natural products. It is a free-radical scavenger, which may explain its cancer preventive properties.