A&P CH24 Metabolism

• METABOLISM: sum of all biochemical reactions inside a cell involving nutrients

  • ANABOLISM: SYNTHESIS of large molecules from small ones

    • Synthesis of proteins from amino acids

  • CATABOLISM: HYDROLYSIS of complex structures to simpler ones

    • Breakdown of proteins into amino acids

• CELLULAR RESPIRATION: food molecules are BROKEN DOWN IN CELLS

  • Some of the energy released used to power ATP synthesis

    • Glycolysis, Citric Acid Cycle, Oxidative Phosphorylation

  • Energy can be stored in glycogen (liver & muscles) and fats (adipose tissue)

• PHOSPHORYLATION: ADP → ATP

  • Phosphorylated molecules become activated to perform cellular functions

1. Substrate Level Phosphorylation

2. Oxidative Phosphorylation

Three stages in processing nutrients:

Stage 1: Digestion, absorption, & transport to tissues

Stage 2: Cellular processing (in cytoplasm)

• SYNTHESIS of lipids, proteins, and glycogen, or

• CATABOLISM (glycolysis) into PYRUVIC ACID and ACETYL CoA

Stage 3: OXIDATIVE of intermediates into CO2, water, and ATP

• Occurs in MITOCHONDRIA

• Cellular respiration consists of glycolysis of stage 2 and all of stage 3

• OXIDATION REACTIONS: involve the gain of oxygen or loss of hydrogen atoms

• OXIDATION REDUCTION (redox) REACTIONS

  • Oxidized substances LOSE electrons and energy

  • Reduced substances GAIN electrons and energy

  • Redox reactions are catalyzed by enzymes that usually require a B VITAMINS COENZYME

    • Dehydrogenases catalyze removal of hydrogen atoms

    • Oxidases catalyze transfer of oxygen

      • “--ases” = enzymes

      • Two important coenzymes act as hydrogen (or electron) acceptors in oxidative pathway

1. Nicotinamide adenine dinucleotide (NAD+)

   1. NIACIN

2. Flavin adenine dinucleotide (FAD)

   1. RIBOFLAVIN

ATP Synthesis

• Two mechanisms are used to make ATP from captured energy that is liberated during cellular respiration

1. SUBSTRATE–LEVEL PHOSPHORYLATION

   1. High-energy phosphate groups are directly transferred from phosphorylated substrates to ADP

   2. Occurs TWICE in glycolysis and ONCE in Krebs cycle

      1. Necessary enzymes are in cytosol for glycolysis and in mitochondria for Krebs cycle

2. OXIDATIVE PHOSPHORYLATION

   1. More complex process, but produces THE MOST ATP

   2. CHEMIOSMOTIC PROCESS: couples movement of substances across membranes to chemical reactions

      1. Energy released from oxidation of food is used to pump H+ across inner mitochondrial membrane, creating a steep H⁺ concentration gradient

• As H+ flows back through ATP synthase membrane channel protein, energy from flow is used to convert ADP & INORGANIC PHOSPHATE (Pi) → ATP

Carbohydrate Metabolism

• When glucose enters a cell, it is phosphorylated to glucose-6-phosphate

  • Most cells lack enzymes for reverse reaction, so glucose becomes trapped inside cell

    • Only cells in intestine, kidney, and liver can reverse reaction and release glucose

• Keeps intracellular glucose concentration LOW, which ensures continued glucose entry

Oxidation of Glucose:

C₆H₁₂O_{6 =}

C₆H₁₂O₆ + 6O₂ → 6H₂O (WATER) + 6CO₂ (CARBON DIOXIDE) + 32 ATP + HEAT

Complete glucose catabolism requires three pathways:

1. GLYCOLYSIS

2. CITRIC ACID CYCLE / KREBS CYCLE

3. ELECTRON TRANSPORT CHAIN & OXIDATIVE PHOSPHORYLATION

Glycolysis

• Also called glycolytic pathway

• Involves 10-step pathway

• ANAEROBIC: Occurs despite presence / absence of O2

• Occurs in CYTOSOL (outside of cell)

• Glucose is broken into 2 PYRUVIC ACID MOLECULES 

• Three major phases

  • Phase 1: Sugar activation

  • Phase 2: Sugar cleavage

  • Phase 3: Sugar oxidation and ATP formation

• Although 4 total ATPs are made, the 2 ATPs needed to prime system in phase 1 must be subtracted

Final products of glycolysis are:

• 2 PYRUVIC ACID 

• 2 reduced NAD⁺ (NADH + H⁺)

• NET GAIN → 2 ATP

• For glycolysis to continue, more NAD+ must be present to accept more hydrogen atoms

  • Supply of NAD+ is LIMITED

    • NADH must donate its accepted hydrogen atoms to become NAD+ again to be free to pick up more H+ so glycolysis can continue

      • If OXYGEN is present, NADH will transfer its H to proteins in ELECTRON TRANSPORT CHAIN

        • Occurs in MITOCHONDRIA

      • If NO OXYGEN is present, NADH will give hydrogen atoms back to pyruvic acid, reducing (building) it to LACTIC ACID

Fate of lactic acid

• Some may leave cell and be picked up by liver, which can convert it back to glucose-6-phosphate

• Some may be oxidized back to pyruvic acid when oxygen becomes available can then enter AEROBIC PATHWAYS

• As you run fast your muscles burn more carbs and produce more lactic acid, which 

• Quickly breaks down into lactate and HYDROGEN ions.

• The hydrogen ions are bad because they 

  • LOWER pH your muscles

    • Decreasing muscle efficiency, and causes BURNING SENSATION

  • Prolonged anaerobic metabolism can lead to ACID–BASE problems

• Glycolysis results in FASTER ATP production than aerobic respiration, but yields FAR LESS ATP

Oxidation of Glucose – Citric Acid Cycle

• Also called KREBS CYCLE

• Occurs in MITOCHONDRIAL MATRIX

• Fueled by PYRUVIC ACID from glucose breakdown and FATTY ACIDS from fat breakdown

• Pyruvic acid must be actively transported into mitochondria because it is a charged molecule

• Once inside mitochondria, pyruvic acid enters transitional phase

• Transitional phase is where each pyruvic acid is converted to acetyl coenzyme A (acetyl CoA) in three steps:

  • DECARBOXYLATION: 1 carbon from pyruvic acid is removed, producing CO2 gas, which diffuses into blood to be expelled by lungs

  • OXIDATION: remaining 2-C fragment is oxidized to acetic acid by removal of H atoms

    • H is picked up by NAD+

  • FORMATION OF ACETYL CoA: acetic acid combines with coenzyme A to form acetyl CoA

Now acetyl CoA…

• Coenzyme A shuttles acetic acid (Acetyl CoA) and binds to oxaloacetate/oxaloacetic acid

  • Produces citric acid (hence the name citric acid cycle)

  • Oxaloacetate are like the “door men” for CAC but they have a lot of other jobs – Urea cycle, gluconeogenesis, fatty acid synthase

• Consists of 8 STEPS - acetic acid is decarboxylated and oxidized into various keto acid intermediates

  • Final step: oxaloacetate is regenerated

    • Cycle goes around AGAIN

For every 1 cycle…

• 2 CO2 from decarboxylation

• 3 NADH

• 1 FADH

• 1 substrate level ATP

But we have 2 Pyruvic Acids!!!!!!

• 4 CO2 from decarboxylation

• 6 NADH

• 2 FADH

• 2 substrate level ATP

Electron transport chain

• Respiratory Chain

  • Transfer of high energy electrons from NADH and FADH to oxygen

• ETC pumps H⁺ across membrane to create PROTON GRADIENT

  • To make 1 ATP, 3 protons must pass through inner membrane space

• Some H+ combine with O2 to produce water

• NADH enters at Complex I

• FADH enters at Complex II

  • Use a shuttle system to go from one complex to the next (coenzyme Q and cytochrome C)

Step by step

• Complex I: NADH enters; 4 protons pumped into inner membrane space

• Complex II: FADH enters; 0 protons pumped out

• Complex III: 2 or 4 protons pumped out

• Complex IV: 2 or 4 protons pumped out; 2 water molecules produced

  • Electrons for water come from cytochrome C

• Complex V: ATP synthase (chemiosmosis)

• Great affinity for electrons… only going to go from one complex to the next (unidirectional)

• 2 electrons shuttled each time

Summary of ATP production

• FLOW OF ENERGY:  Glucose → NADH + H+ → ETC → proton gradient energy → ATP

Net energy gain from complete oxidation of 1 glucose molecule:

1. Substrate-level phosphorylation: 4 ATPs

• 2 from glycolysis and 2 from citric acid cycle

2. Oxidative phosphorylation: 28 ATPs 

• For each NADH + H⁺ brought in, proton gradient generates 2.5 ATPs

  • 10 NADH + H+ are made, so 25 ATPs

• For every FADH2 brought in, only 1.5 ATPs are created

  • 2 FADH2 are made, so 3 ATPs created

• Totals between substrate-level phosphorylation and oxidative phosphorylation equal 32 ATPs

• But….energy is required to move NADH + H+ generated in glycolysis into mitochondria, which uses up 2 ATPs, so final total is 30 ATPs produced

• There is still uncertainty on final total

Glycogenesis, Glycogenolysis, and Gluconeogenesis

• Cells cannot store large amounts of ATP

• Rising intracellular levels of ATP INHIBIT glucose catabolism and promote GLYCOGEN or FAT FORMATION 

Glycogenesis

• Glycogen can be formed with excess glucose

• Mostly occurs in LIVER and SKELETAL MUSCLE CELLS

Glycogenolysis

• Breakdown of glycogen via glycogen phosphorylase in response to LOW BLOOD GLUCOSE

  • Enzyme splits and phosphorylates terminal glucose on glycogen

  • Forms glucose-1-phosphate, which is converted to glucose-6-phosphate, which then can enter glycolysis in that cell

  • Glucose can enter bloodstream to be used by other cells

Gluconeogenesis

• Process of forming NEW (neo) glucose from noncarbohydrate sources

• Occurs in the LIVER

• Glucose can be formed from GLYCEROL and AMINO ACIDS when blood glucose levels drop

• Protects against damaging effects of low blood glucose levels HYPOGLYCEMIA

  • Especially important for nervous system

24.5 Lipid Metabolism

• Lipids provide a greater energy yield than from glucose or protein catabolism

  • Fat catabolism yields 9 kcal per gram versus 4 kcal per gram of carbohydrate or protein

• Most products of fat digestion are transported in lymph as chylomicrons

• Hydrolyzed by endothelial enzymes into FATTY ACIDS and GLYCEROL

Oxidation of Glycerol and Fatty Acids

• Only TRIGLYCERIDES are routinely oxidized for energy

• Two building blocks of triglycerides are oxidized separately

1. Glycerol breakdown

   1. Glycerol is broken down into glyceraldehyde 3-phosphate (same as in glycolysis), which then enters citric acid cycle

      1. ATP yield is roughly half that of glucose because glyceraldehyde is only a half glucose

      2. Yields 15 ATP / GLYCEROL

2. Fatty acid breakdown

   1. Fatty acids undergo beta oxidation in MITOCHONDRIA:

      1. Fatty acid chains are broken into two-carbon acetic acid fragments, and coenzymes (FAD and NAD+) are reduced in process

      2. Acetic acid fragment fuses with CoA to form acetyl CoA, which enters citric acid cycle

         1. Reduced coenzymes enter electron transport chain

      3. Referred to as “beta” oxidation because two carbons are broken off fatty acid chain, allowing third-position carbon to be oxidized

Lipogenesis

• LIPOGENESIS: triglyceride synthesis that occurs when cellular ATP and glucose levels are HIGH

• Dietary glycerol and fatty acids not needed for energy are stored as triglycerides

  • 50% is stored in ADIPOSE TISSUE; other 50% is deposited in other areas

• Glucose is easily converted to fat because acetyl CoA is an intermediate in glucose catabolism and the starting point for fatty acid synthesis

Lipolysis

• LIPOLYSIS: breakdown of STORED FATS into glycerol and fatty acids; reverse of lipogenesis

  • Fatty acids are actually preferred by liver, cardiac muscle, RESTING skeletal muscle for fuel

  • Lipolysis is accelerated when carbohydrate intake is INADEQUATE

• Beta oxidation of the released fatty acids results in production of large amounts of ACETYL CoA

  • Acetyl CoA can enter citric acid cycle only if enough intermediates (oxaloacetic acid) are available

    • If intermediates are not available, acetyl CoA can accumulate

• Accumulated acetyl CoA can be converted by ketogenesis in liver to KETONE BODIES

Clinical – Homeostatic Imbalance 24.2

• Accumulation of ketone bodies in blood can lead to KETOSIS

  • Common in starvation, unwise dieting, or diabetes mellitus

  • Ketone bodies are also excreted in URINE

• Ketones are ACIDIC, so a buildup of these molecules can lead to metabolic acidosis, which can cause DANGEROUSLY LOW pH levels

  • Patient’s breath can smell FRUITY from vaporizing acetone

  • Breathing becomes rapid as lungs try to release CO2 to RAISE pH

Synthesis of Structural Materials

• Lipids play many roles in structural materials

  • Phospholipids are used for cell membranes and MYELIN

  • Cholesterol is used for cell membranes and steroid hormone synthesis

• In addition, the LIVER:

  • Synthesizes transport LIPOPROTEINS (HDLs / LDLs) for cholesterol and fats

    • HDLs are good (recyclers)

    • LDLs are bad (litterers)

  • Synthesizes cholesterol from acetyl CoA

• Uses cholesterol to form BILE SALTS

24.6 Protein Metabolism

• Proteins deteriorate, so they need to be continually broken down and replaced

• Amino acids are recycled into new proteins or different compounds

• PROTEINS are NOT STORED IN BODY

  • When dietary proteins are in excess, amino acids are:

• Oxidized for ENERGY

• Converted to FAT for storage

Degradation of Amino Acids

• Goal is to produce molecules that can be used for energy in CITRIC ACID CYCLE or converted to GLUCOSE

• First step in amino acid breakdown is DEAMINATION, whereby NH2 (amine group) is removed, then converted into:

  • One of keto acid intermediates of citric acid cycle

Three events of amino acid degradation

1. TRANSAMINATION

2. OXIDATIVE DEAMINATION

3. KETO ACID MODIFICATION

1. Transamination

• Many amino acids can transfer their amine group to α-ketoglutaric acid, transforming it into glutamic acid

  • As a result, original amino acid becomes a KETO ACID

2. Oxidative deamination

• In liver, amine group of glutamic acid is removed as ammonia (NH3)

• α-ketoglutaric acid is regenerated

• NH3 then combines with CO2 to form UREA and water

  • UREA is released to blood and excreted in urine

• This urea cycle helps rid body of toxic ammonia

3. Keto acid modification

• Keto acids formed from transamination are altered to produce metabolites that can enter citric acid cycle

  • Major metabolites produced:

    • α-ketoglutaric acid

    • Oxaloacetic acid

• Glycolysis reactions are reversible, so pyruvic acid metabolites formed can be reconverted to glucose

  • Contributes to GLUCONEOGENESIS

Protein Synthesis

• Amino acids are most important ANABOLIC NUTRIENTS

  • Form all proteins as well as bulk of functional molecules

• Protein synthesis that occurs on RIBOSOMES is hormonally controlled

  • growth hormone, thyroid hormone, sex hormones

• Synthesis requires complete set of amino acids

  • Essential amino acids must be acquired in diet – How many? → 9

• During our lifetime, depending on body size, we can synthesize 225–450 kg (500–1000 lbs) of protein