USMLE - Metabolism Part 1
Glycolysis is a 10-step metabolic pathway that breaks down glucose into pyruvate, producing ATP and NADH. Key regulatory enzymes include hexokinase/glucokinase, phosphofructokinase (PFK), and pyruvate kinase. The pathway splits glucose into two molecules of G3P, which are further processed to generate energy.
Glycolysis Pathway
Glucose –> [Hexokinase/Glucokinase] –> G6P –> F6P –> [PFK] –> F-1,6-bP –> DHAP + G3P
DHAP –> G3P
G3P ->->-> PEP –> [Pyruvate Kinase] –> Pyruvate
Key Terms
Glycolysis Pathway
Glucose –> [Hexokinase/Glucokinase] –> G6P –> F6P –> [PFK] –> F-1,6-bP –> DHAP + G3P
DHAP –> G3P
G3P ->->-&g...
Glycogen synthesis pathway
Glycogen breakdown pathway
G6P –> G1P –> [UDP Glucose Pyrophosphorylase] –> UDP-Glucose –> [Glycogen Synthase] –> Glycogen –> [Branching Enzymes] –> Bran...
How does Galactose enter Glycolysis?
Galactose –> [Galactokinase] –> Galactose-1-Phosphate –> [Galactose-1-Phosphate Uridyltransferase] –> G1P –> G6P
HMP Shunt pathway
G6P –> [G6PD] –> 6-phosphogluconolactone ->->-> Ribulose-5-Phosphate ->->-> [Transketolase + Thiamine] ->->-> F6P<...
How does Fructose enter glycolysis
Fructose –> [Fructokinase] –> F1P –> [Aldolase B] –> DHAP + Glyceraldehyde
Both DHAP and Glyceraldehyde are converted into G3P
Gluconeogenesis pathway
Pyruvate –> [pyruvate carboxylase + Biotin] –> Oxaloacetate –> [PEP carboxykinase] –> PEP ->->-> F-1,6-bP –> [F-1,6-bisphos...
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| Term | Definition |
|---|---|
Glycolysis Pathway | Glucose –> [Hexokinase/Glucokinase] –> G6P –> F6P –> [PFK] –> F-1,6-bP –> DHAP + G3P DHAP –> G3P G3P ->->-> PEP –> [Pyruvate Kinase] –> Pyruvate |
Glycogen synthesis pathway Glycogen breakdown pathway | G6P –> G1P –> [UDP Glucose Pyrophosphorylase] –> UDP-Glucose –> [Glycogen Synthase] –> Glycogen –> [Branching Enzymes] –> Branched Glycogen Glycogen –> [Glycogen Phosphorylase] –> G1P –> G6P Branched Glycogen –> [Debranching enzymes] –> Limit Dextrin –> [Debranching enzymes] –> Linear Glycogen |
How does Galactose enter Glycolysis? | Galactose –> [Galactokinase] –> Galactose-1-Phosphate –> [Galactose-1-Phosphate Uridyltransferase] –> G1P –> G6P |
HMP Shunt pathway | G6P –> [G6PD] –> 6-phosphogluconolactone ->->-> Ribulose-5-Phosphate ->->-> [Transketolase + Thiamine] ->->-> F6P |
How does Fructose enter glycolysis | Fructose –> [Fructokinase] –> F1P –> [Aldolase B] –> DHAP + Glyceraldehyde Both DHAP and Glyceraldehyde are converted into G3P OR… Fructose –> [Hexokinase] –> F6P |
Gluconeogenesis pathway | Pyruvate –> [pyruvate carboxylase + Biotin] –> Oxaloacetate –> [PEP carboxykinase] –> PEP ->->-> F-1,6-bP –> [F-1,6-bisphosphatase] –> F6P –> G6P –> [G6Phosphatase] –> Glucose |
Cholesterol synthesis pathway | Acetyl CoA –> Acetoacetyl-CoA –> HMG CoA –> [HMG CoA Reductase] –> Mevalonate ->->-> Cholesterol |
β-hydroxybutyrate synthesis pathway | 2Acetyl CoA –> Acetoacetyl CoA –> HMG CoA –> Acetoacetate Acetoacetate + NADH –> [β-hydroxybutyrate Dehydrogenase] –> β-hydroxybutyrate + NAD Reaction is reversed in brain to produce NADH |
TCA cycle Pathway | “Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate” Pyruvate –> [Pyruvate Dehydrogenase] –> Acetyl CoA Acetyl CoA + Oxaloacetate –> [Citrate Synthase] –> Citrate –> Isocitrate –> [Isocitrate dehydrogenase] –> α-ketoglutarate –> [α-ketoglutarate dehydrogenase + Thiamine] –> Succinyl-CoA –> Succinate –> Fumarate –> Malate –> Oxaloacetate |
How do odd chain fatty acids and VMIT enter TCA cycle | Propinoyl-CoA –> [Biotin] –> Methylmalonyl CoA –> [B12] –> Succinyl CoA |
How much ATP does Glucose produce in Heart and Liver | Aerobic Metabolism produces 32 ATP via malate-aspartate shuttle |
How much ATP does Glucose produce in Muscle? | Aerobic Metabolism produces 30 ATP via Glycerol-3-Phosphate shuttle |
How much glucose does Anaerobic Glycolysis produce | 2 ATP per Glucose |
Carrier Molecule ATP carries | Phosphoryl groups |
Carrier Molecules NADH, NADPH, and FADH2 carries | Electrons |
Carrier Molecules Coenzyme A, Lipamine carries | Acyl Groups |
Carrier Molecule Biotin carries | CO2 |
Carrier Molecule THF carries | 1 carbon units |
Carrier Molecule SAM carries | CH3 groups |
Carrier Molecule TPP carries | Aldehydes |
NADH vs NADPH | NAD is Catabolic NADP is Anabolic |
NADPH What process produces it? What kind of reaction? What reactions is it used in? | Produces in HMP shunt Reduction reactions Used in anabolic processes (Steroid and Fatty Acid Synthesis), Respiratory Burst, P450, Glutathione Reductase |
Hexokinase Reaction Where is it? Affinity Capacity Regulation | Glucose --> G6P Ubiquitous High Affinity (low Km) Low Capacity (low Vmax) Uninduced by insulin. Feedback inhibition by G6P |
Glucokinase Reaction Where is it? Affinity Capacity Regulation | Glucose --> G6P Liver and β cells of Pancreas Low Affinity (high Km) High Capacity (high Vmax) "GLUcokinase is a GLUtton, it cannot be satisfied" Induced by Insulin. |
General glucose regulation | At low [glucose], hexokinase sequesters glucose in the tissues. At high [glucose], excess glucose is stored in the liver |
Net Glycolysis Reaction | Glucose + 2P + 2ADP + 2NAD --> 2Pyruvate + 2ATP + 2NADH + 2H + 2H2O |
F-2,6-BP Reaction that produces it and degrades it What does it activate and what are the consequences of that? Pathways in Fed vs Fasting state? | F6P --> [PFK-2] --> F-2,6-BP --> [FBPase2] --> F6P F-2,6-BP activates PFK1 and pushes balance towards glycolysis PFK2 is active in fed state Fasting state: Glucagon --> ↑cAMP --> ↑PKA --> ↑ FBPase2, ↓ PFK2, less glycolysis Fed state: Insulin --> ↓cAMP --> ↓PKA --> ↓ FBPase2, ↑ PFK2, more glycolysis |
Pyruvate Dehydrogenase Complex Reaction # of enzymes # of cofactors with names What activates it? What complex is similar? Regulation | Pyruvate + NAD + CoA --> Acetyl-CoA + CO2 + NAD 5 cofactors (TPP, FAD, NAD, CoA, Lipoic Acid) "Tender Loving Care For Nancy" Activated by ↑ NAD/NADH ratio, ↑ADP, ↑Ca α-ketoglutarate dehydrogenase complex is similar Inhibited by ATP, AcetylCoA, and NADH |
Arsenic Mechanism of toxicity Findings | Inhibits Lipoic acid | Vomiting, rice water stool, garlic breath |
Pyruvate Dehydrogenase Complex Deficiency Mutation PathoPhys Findings Treatment | X linked gene for E1-α subunit Backup of substrates (pyruvate and alanine) --> lactic acidosis Neurological defects starting in infancy Intake of ketogenic nutrients (high fat or high in lysine and leucine) "Lysine and Leucine - the onLy pureLy Ketogenic AA" |
Pyruvate Metabolism Pathway | Pyruvate ↔ [ALT w/ B6] ↔ Alanine which carries amino groups to liver from muscle Pyruvate + CO2 + ATP ↔ [Pyruvate Carboxylase w/ Biotin] ↔ Oxaloacetate which can replenish TCA cycle or be used in gluconeognesis Pyruvate + NAD ↔ [Pyruvate Dehydrogenase] ↔ NADH + CO2 + Acetyl Coa Pyruvate + NADH ↔ [Lactic Acid Dehydrogenase w/ B3] ↔ NAD + Lactic Acid which is the end product of anaerobic glycolysis (major pathway in RBCs, Leukocytes, Kidney Medulla, Lens, Testes, Cornea) |
What does the TCA cycle produce? | 3NADH, 1FADH2, 2CO2, and 1GTP per 1Acetyl CoA |
Where does the TCA cycle occur? | In the Mitochondria |
Regulation of Citrate Synthase | Inhibited by ATP |
α-ketoglutarate dehydrogenase regulation | Inhibited by SuccinylCoA, NADH, and ATP |
What reactions of the Krebs Cycle produce NADH | Isocitrate --> α-ketoglutarate α-ketoglutarate --> Succinyl CoA Malate --> Oxaloacetate |
What reactions of the Krebs Cycle produce GTP | Succinyl CoA --> Succinate |
What reactions of the Krebs Cycle produce FADH2 | Succinate --> Fumarate |
How does NADH get into the Mitochondria? | Malate Aspartate or Glycerol-3-Phosphate shuttle |
Malate Aspartate Shuttle | Cytoplasm: NADH + OAA --> NAD + Malate Malate/α-ketoglutarate antiporter transports Malate into matrix Matrix: NAD + Malate --> OAA + NADH OAA + Glutamte --> Aspartate + α-ketoglutarate Asp/Glu antiporter transports Asp into cytoplasm |
Glycerol-3-Phosphate Shuttle | Cytoplasm: NADH + DHAP --> NAD + G3P @ Mito inner membrane: G3P + FAD --> [G3PDH] --> DHAP + FADH2 |
ETC Complex I Reaction Pumping Inhibitor? | NADH --> NAD and CoQ H pumped out Rotenone |
ETC Complex II Name Reaction Pumping? | Succinate Dehydrogenase FADH2 --> FAD and CoQ No protons pumped thus lower energy level |
Complex III Reaction Pumping Inhibitor | CoQ transfers electrons to Cytochrome c H pumped out Antimycin A |
Complex IV Reaction Pumping Inhibitor | 2 Cytochrome c gives electrons to 1 O2 to produce H2O H pumped out Cyanide and CO |
Complex V Reaction Pumping Inhibitor | ADP + P --> ATP H moves into matrix Oligomycin |
How many ATP does NADH produce? | 2.5 |
How many ATP does FADH produce? | 1.5 |
Uncoupling agents MoA PathoPhys What happens to ATP synthesis and the ETC? What is produced? Names | ↑ permeability of membrane ↓ proton gradient and ↑ O2 consumption ATP synthesis stops but ETC continues Heat is produced 2,4-DNP, Aspirin (fevers occur after OD), Thermogenin in brown fat |
Irreversible Enzymes in Gluconeognesis | Enzyme, Reaction, Location | "Pathways Produce Fresh Glucose" Pyruvate Carboxylase, Pyruvate --> OAA, Mito PEP carboxykinase, OAA --> PEP, Cytoplasm F-1,6-bPase, F-1,6,bP --> F6P, Cytoplasm G6Pase, G6P --> Glucose, ER |
Pyruvate Carboxylase Reaction Regulation | Pyruvate + ATP --> OAA + ADP | Requires Biotin. Activated by Acetyl-CoA |
Required cofactor of PEP Carboxykinase | GTP |
What tissues are capable of gluconeogenesis | Occurs primarily in Liver | Also in Kidney and Intestinal Epithelium |
What is the result of a deficiency in the enzymes of Gluconeognesis? | Hypoglycemia |
What tissues care not capable of gluconeogenesis? Why? | Muscles because they lack G6Pase |
Can fatty acids participate in gluconeogenesis? | Odd chain fatty acids yield propinoyl-CoA which enters TCA cycle as succinyl CoA and can undergo gluconeogenesis Even chain fatty acids cannot produce new glucose since they yield only acetyl CoA equivalents |
HMP Shunt What does it produce? What are the phases? Where does it occur? ATP? Sites where it happens? | Provides a source of NADPH from G6P and Ribose for nucleotide synthesis and glycolytic intermediate Occurs in Cytoplasm No ATP is used or produced Sites of FA or steroid synthesis: Lactating mammary glands, Liver, Adrenal Cortex Also RBCs |
NADPH in RBCs | Glutathione reduction |
Oxidative reaction of HMP shunt Pathway Regulation Reversible? | G6P + NADP --> [G6PDH] --> NADPH + CO2 + Ribulose-5-Phosphate Inhibited by NADPH Irreversible rate limiting step |
Nonoxidative reaction of HMP shunt Pathway Regulation Reversible? | Ribulose-5-Phosphate --> [Phosphopentose isomerase, Transketolases] ->->-> Ribose-5-Phosphate + G3P + F5P Requires B1 Reversible |
Respiratory Burst AKA Cells that do it? Role in what system? Function | Oxidative Burst Neutrophils and Monocytes Plays an important role in the immune system response Rapid release of Reactive Oxygen Intermediates |
Oxidative Burst Pathway | O2 + NADPH --> [NADPH Oxidase] --> O2-* + NADP O2-* --> [Superoxide dismutase] --> H2O2 H2O2 + Cl --> [Myeloperoxidase] --> HOCl* HOCl* kills bacteria |
Chronic Granulomatous Diseases Deficiency Can they fight infection? How? What are they at risk for? | NADPH oxidase deficiency Can use H2O2 generated by invading organisms to fight disease At risk for infection by catalase + species (S aureus and Aspergillus) |
How is H2O2 neutralized by bacteria? | H2O2 --> [bacterial catalases] --> H2O and O2 |
How is H2O2 neutralized in human cells? | H2O2 + Glutathione-SH (reduced) --> [Glutathione Peroxidase] --> H2O + GSSG (oxidized) GSSG + NADPH --> [Glutathione Reductase] --> GSH + NADP NADP + G6P --> [G6PDH] --> NADPH + 6-Phosphogluconate |
Why is it necessary to keep Glutathione reduced? What keeps it reduced? | Reduced Glutathione can detoxify free radicals | NADPH keeps it reduced |
G6PDH Reaction What happens if there is a deficiency? | G6P + NADP --> 6PG + NADPH | Deficiency results in ↓ NADPH |
PathoPhys of G6PDH Deficiency | Low NADPH in RBCs leads to hemolytic anemia, due to poor RBC defense against oxidizing agents (Fava Beans, Sulfonamides, Primaquine, AntiTB drugs) Infections can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage) |
G6PDH Deficiency Inheritance Epidemiology What does it confer? Histo | X linked recessive Most common human enzyme deficiency. More prevalent among blacks Confers Malarial Resistance Heinz Bodies: Oxidized Hemoglobin precipitated within RBCs Bite Cells: Phagocytic removal of Heinz bodies by splenic macs "Bite into some Heinz Ketchup" |
Essential Fructosuria Mutation Inheritance Danger? Symptoms? Findings | Defect in Fructokinase Autosomal Recessive Benign Asymptomatic since fructose is not trapped in cells Fructose appears in blood and urine |
Fructose intolerance Mutation Inheritance What accumulates and what are the consequences? Symptoms Treatment | Defect in Aldolase B Autosomal Recessive F1P accumulates --> ↓ in available P --> Inhibition of glycogenolysis and gluconeogenesis Hypoglycemia, Jaundice, Cirrhosis, Vomiting ↓ intake of fructose and sucrose (glucose + fructose) |
Galactokinase Deficiency Mutation What accumulates Inheritance How bad? Symptoms | Mutation in Galactokinase Galactitol accumulates Autosomal Recessive Mild Condition Galactose in blood and urine, Infantile Cataracts. May initially present as failure to track objects or to develop a social smile |
Classic Galactosemia Mutation? Inheritance What leads to damage? Symptoms Treatment | Galactose-1-Phosphate Uridyltransferase Autosomal Recessive Damage caused by accumulation of toxic substances (including galactitol) which accumulates in the lens of the eye "I Just Fed Her Milk" Failure to thrive, Jaundice, Hepatomegaly, Infantile Cataracts, Mental Retardation Exclude galactose and lactose (galactose + glucose) from diet |
How is Galacititol made? | Galactose --> [Aldose Reductase] --> Galactitol | Made when [galactose] is high |
Sorbitol Why is it made? What is it? Pathway What else can be made into it? | Made as an alternative method for trapping glucose in the cell Alcohol counterpart to glucose Glucose + NADPH --> [Aldose Reductase] --> Sorbitol + NAD High galactose can also result into conversion into Sorbitol |
What is the fate of Sorbitol Pathway What tissues have an insufficient amount of this enzyme? | Sorbitol + NAD --> [Sorbitol Dehydrogenase] --> Fructose + NADH Schwann cells, Retina, and Kidneys only have Aldose Reductase and are thus at risk for osmotic damage (Cataracts, Retinopathy, Peripheral Neuropathy) |
Which tissues have both Aldose Reductase and Sorbitol Dehydrogenase? | Liver, Ovaries, Seminal Vesicles |
Lactase Deficiency What causes it? Epidemiology Self Limiting Kind? Symptoms Treatment | Age Dependent or Hereditary Lactose Intolerance due to loss of brush border enzyme African Americans and Asians May follow gastroenteritis Bloating, cramps, osmotic diarrhea Avoid dairy products or add lactase pills to diet |
What kind of AA are found in proteins? | Only L form |
Essential AA What are they? Glucogenic Glucogenic/Ketogenic Ketogenic | Need to be supplied in the diet Met, Val, His Ile, Phe, Thr, Trp "WIFT" Leu, Lys |
Acidic AA | Asp and Glu |
Basic AA | Arg, Lys, and His Arg is the most basic His has no charge at body pH |
Which AA are required during periods of growth? | Arg and His |
Purpose of Urea Cycle | Excrete NH4+ from AA catabolism |
Urea Cycle Pathway | "Ordinary, Careless, Crappers Are Also Frivolous About Urination" Mito: NH4 + CO2 + 2ATP --> [Carbamoyl Phosphate Synthase I] --> Carbamoyl phosphate Carbamoyl Phosphate + Ornithine --> [Ornithine transcarbamoylase] --> Citrulline Cyto: Citrulline + Aspartate + ATP --> [Argininosuccinate Synthetase] --> Argininosuccinate (+ AMP) --> [Argininosuccinase] --> Arginine and Fumarate Arginine + H2O --> Urea + Ornithine |
What molecules make up Urea | NH4+, CO2, Asp |
Alanine Cycle | Muscle: Glucose --> Pyruvate --> Alanine Liver: Alanine --> Pyruvate --> Glucose |
Cori Cycle | Muscle: Glucose --> Pyruvate --> Lactate Liver: Lactate --> Pyruvate --> Glucose |
How does NH3 go from muscles to liver? | What vitamin is important for this process? | Muscle: AA (NH3) + α-ketoglutarate --> Glutamate (NH3) + α-ketoacids Glutamate (NH3) + Pyruvate --> α-ketoglutarate + Ala (NH3) Liver: Ala (NH3) + α-ketoglutarate --> Pyruvate + Glutamate (NH3) Glutamate --> Urea BitB6 vital to Alpha Ketoglutarate |
Hyperammonemia Etiology PathoPhys | Acquired (liver disease) or Hereditary (urea cycle enzyme deficiency) Excess NH4+ depletes α-ketoglutarate leading to inhibition of TCA cycle |
Hyperammonemia Presentation Treatment | Tremor (Asterixis), Slurring Speech, Somnolence, Vomiting, Cerebral Edema, Blurring Vision Limit protein diet Give benzoate or phenylbutyrate which bind AA and lead to excretion Lactulose to acidify the GI tract and trap NH4 for excretion |
Ornithine Transcarbamoylase Deficiency Frequency Inheritance Time of onset PathoPhys Findings | Most common urea cycle disorder X linked recessive (vs other urea cycle enzyme deficiencies which are AR) Evident in first few days of life but may present with late onset Body cannot eliminate ammonia. Carbamoyl phosphate builds up and converted into orotic acid (party of pyrimidine synthesis pathway) Orotic acid in blood and urine, ↓ BUN, Hyperammonemia |
Products made from Phenylalanine | Phe --> [BH4] --> Tyrosine --> [BH4] --> DOPA --> [B6] --> DA --> [VitC] --> NE --> [SAM] --> Epi Tyrosine --> Thyroxine DOPA --> Melanin |
Products made from Tryptophan | Trp --> [B6] --> Niacin --> NAD | Trp --> [BH4] --> 5HT --> Melatonin |
Products made from Histidine | His --> [B6] --> Histamine |
Products made from Glycine | Gly --> [B6] --> Porphyrin --> Heme |
Products made from Arginine | Arg --> Creatine Arg --> Urea Arg --> Nitric Oxide |
Products made from Glutamate | Glu --> [B6] --> GABA | Glu --> Glutathione |
Catecholamine Synthesis Pathway | Phe + THB --> [Phe Hydoxylase] --> Tyr + DHB Tyr + DHB --> [Tyr Hydroxylase] --> DOPA + DHB DOPA --> [DOPA Decarboxylase w/ VitB6] --> DA --> [DA-β-Hydroxylase w/ VitC] --> NE --> [Phenylethanolamine N-methyltransferase] --> Epi |
Phenylethanolamine N-methyltransferase Reaction Regulation | NE --> Epi | Activated by Cortisol |