METABOLISM - All chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells.

Enzyme-catalyzed reactions - Allow organisms to grow and reproduce, maintain their structures, and respond to their environments.- To extract energy from nutrients or solar energy- To synthesize the building blocks that make up the large molecules of life: proteins, fats, carbohydrates, nucleic acids, and combinations of these substances;

Principles of Metabolism- Fuels are degraded and large molecules are constructed in a series of linked reactions- ATP links energy-releasing pathways with energy requiring pathwaysCatabolism breakdown; produces energyAnabolism synthesis; build-up; makes use of energy- Metabolic pathways are highly regulated

Rate-Limiting enzyme/committed enzyme- Avoids futile cycling by regulation of metabolic pathways- Usually (not always) the primary enzyme, - Catalyzes the first irreversible reaction in a metabolic pathwayIrreversible step- Spontaneous reaction, which requires a big (delta G)- Enzyme, which catalyzes the forward reaction, cannot catalyze the reverse reaction- An enzyme can be used to catalyze a reaction that produces an intermediate from a substrate. That same enzyme cannot be used to return the intermediate into its substrate

Metabolic Pathways in the cells always require a series of enzymatic reactions. It cannot happen if theres only 1 enzyme or 1 reaction involved; 1 enzyme should always precede the next enzyme.Michaelis-Menten Constant (Km) will determine which enzyme is going to bind to a substrate; responsible for the specificity of enzymesLOW KM, HIGH AFFINITYFAT - The primary form of potential chemical energy is stored in the body

C. Energy MetabolismBMR (Basal Metabolic Rate)- Amt of energy needed by the whole body during a resting state (sleeping)- Necessary amount to keep vital organs working (heart, hrain, kidneys, blood) Varies according to mental/physical activity, sex, age- Measured in terms of calories- Calorie requirement that a person will utilize depends on the nutrients which are oxidized through metabolic pathways

1. Metabolic Fuels & their PathwaysGLYCOLYSIS CHO and some AAPYRUVATE OXIDATION Some AACITRIC ACID CYCLE Fatty acids, AA=OXIDATIVE PHOSPHORYLATIONCARBOHYDATES- Main source of energy; first line of macronutrients that the cells are going to utilize- Glycogen (Storage form of polysaccharides in animals) only found in 2 organs (liver and muscle)

LIPIDS16C saturated fatty acid, Palmitic Acid- Most common fatty acid in the body is a - More triglycerides can be stored in obese individuals due to expansion of adipose cells

PROTEINS- not considered storage forms of aminoacids (Their principal function is not to provide energy but to provide structure)

ATP & PhosphorylationATP (Adenosine Triphosphate)- Cellular form of energy- Has phosphoanhydride bonds, which makes it capable of supplying energy for cellular activities - Phosphate group attached to carbon 5, other phosphate groups bind to each other through phosphoanhhydride bonds- Energy is specifically derived from the hydrolysis of the phosphoanhydride bonds- ATP can never be stored- 100g in blood ATP is continually synthesizedATP -> ADP + Pi (inorganic phosphate) ATP -> AMP + Pp (pyrophosphate)Resting state : 40 kg of ATP dailyStrenuous exercise: 0.5 kgs/min of ATPPHOSPHORYLATION ATP Production process- ADP is the substrate, PO4 is added

a. Substrate - Level Phosphorylation- Occurs in the cytosol- Need of substrates/ intermediate- Enzyme has ability to capture/harvest inorganic phosphate from cytosol and attach it to ADP, coupled with an intermediate PEP Phosphoenolpyruvate that will be converted into pyruvate (ATP and pyruvate are formed using same enzyme, therefore, substrate - level)

b. Oxidative Phosphorylation- Occurs in the mitochondria- Transfer of high energy phosphate group requires the presence of electrons; electrons will enter mitochondria via proton pump- In the process, the proton pump will allow for the ATP synthase to attach the high energy phosphate bonds to regenerate ATP- Not substrate, but movement of electrons that will propel ATP generation- No involvement of intermediate, but oxygen is the final hydrogen/electron acceptorTissue Specific Metabolism Brain- Dependent on glucose for energy- Neurons are continuously firing; need for glucose is high; adequate supply is needed; amount of glucose is dependent on how often we eatSmall intestine- Site of absorption of monosaccharides (Glucose, Galactose, Fructose).- Travels to liver through portal circulation- Glucose crosses the small intestine through transporters SGLT1, GLUT 5, and GLUT2Fatty acids and cholesterol transported from the small intestines with the use of lipoproteins (Chylomicrons) by means of lymph circulationPancreas- Regulates energy-related metabolic activities- Secretes insulin (fed state) and Glucagon (starved state)Insulin allows transport of glucose to insulin- dependent organsGlucagon mobilizes the glucose in the liver for it to be able to provide the necessary ATP source for the brainLiver Metabolic Hub- Distributes the different nutrients to the different organs

Brain: transports ions to maintain membrane potential; integrates inputs form body and surroundings sends signals to other organsLymphatic System: Carries lipids from intestines to liverAdipose Tissue: Synthesizes, stores, and mobilizes triacyl glycerolsSkeletal Muscle: Uses ATP to do workSmall Intestine: Absorbs nutrients from the diet, moves them into the blood or into the lymphatic systemPortal Vein: Carries nutrients from intestine to liverLiver: Processes fats, CHO, CHON from diet; synthesizes and distributes lipids, ketone bodies and glucose for tissues.Converts excess Nitrogen to UreaPancreas: Secretes insulin and glucagon in response to change to glucose conc.

Principles of Energy MetabolismEnergy metabolism relates energy input in the whole organism to energy expenditure; positive and negative energy balance- There should be a balance between intake and expenditure. If intake > expenditure, balance is tilted to more storage than usage and can lead to obesity or metabolic syndrome- Carbon in fuel molecules is oxidized to CO2 to regenerate ATP from ADP and Pi

HIGH Energy content in metabolic fuelsHIGH Amt of energy expended through endergonic reactions

Acetyl CoA - substrate for Krebs Cycle Krebs Cycle - produce electrons that are transported by NAD and FAD so that they will be able to enter the oxidative pathway in Electron Transport Chain; common pathway

- Metabolic pathways are irreversible- Every MP has a first committed step - All metabolic pathways are regulatedOXIDATION REDUCTION REACTION- Involves the loss or gain of electrons- Use of coenzymes NADH and FADH2- Transfer one or two electrons- Terminal electron acceptors for different organisms (O2, NO3-, Fe3+)

Stage 1 - macromolecules are broken down to monomeric unitsStage 2 - monomeric units undergo oxidation to produce a common product, which is Acetyl CoAStage 3 - oxidative phosphorylation - electrons from Krebs cycle produce ATP; occurs in mitochondria; produces the most ATP compared to other pathways; final acceptor is water

REGULATION OF METABOLISM- Utilization of metabolic fuels by different organs in the human body is controlled at the cellular level as a function of nutrient availability

Allosteric Modulation- Allosteric effectors bring about catalytic modification by binding to the enzyme at distinct allosteric sites.- The hallmark of effectors is that when they bind to enzymes, they alter the catalytic properties of an enzyme's active site.- Vmax can be increased or decreased, or the Km can be raised or lowered

Covalent Modification- Addition of or removal of phosphate or adenylate - Protein kinase- Use of ATP

Gene expression- Important regulatory mechanism of enzymes- Longest to happen; nucleus needs to express the gene, transcribe to mRna, and mRna to ribosome

Endocrine Secretions- Hormones, hypothalamic hormones, adipose tissues (produces adiponectin, lectin)

Amount of Enzymes- Dependent on rate of synthesis/ degradation

Accessibility of Substrates- Compartmentalization/ controlling flux of substrates

Metabolism at Different States 1. Fed State- Organs are active- Consumption of food leads to dietary supply; nutrients will enter the liver; the liver distributes

2. Overnight Fast- Liver will still send glucose to the brain but it's coming from glycogen- Glucose does not come from dietary supply

3. Starved State - Prolonged starvation - glucose still being produced; coming from carbon skeleton of amino acids; amino acids have carbon chains and will be dependent on the side chain of amino acid- Ammonia production; toxic, will cross blood brain barrier and damage neurons; converted to urea, a non toxic form- BUN and creatinine are measured in bloodKetone bodies (from degradation of amino acids) - by products in prolonged starvation