USMLE - Metabolism Part 2
Phenylketonuria (PKU) is caused by a mutation in the enzyme phenylalanine hydroxylase, leading to an inability to convert phenylalanine to tyrosine. As a result, phenylalanine accumulates, and tyrosine becomes an essential amino acid. It is inherited in an autosomal recessive pattern and leads to excess phenylketones in urine.
Tetrahydrobiopterin
Names
What replenishes it?
THB or BH4
| DHB + NADPH --> [Dihydropteridine Reductase] --> THB + NADP
Key Terms
Tetrahydrobiopterin
Names
What replenishes it?
THB or BH4
| DHB + NADPH --> [Dihydropteridine Reductase] --> THB + NADP
Breakdown of Catecholamines
Enzymes
Products
MAO and COMT
DA --> HVA
NE --> NorMetanephrine --> VMA
Epi --> Metanephrine --> VMA
Phenylketonuria
Mutation
Consequences Re AAs
What builds up?
Inheritance
Mutation in Phe Hydroxylase
Tyr becomes essential
Phe builds up leading to excess phenylketones in urine
Autosomal Recessive
Malignant Phenylketonuria
What causes it?
Findings
Decreased THB
| PKU symptoms, but after treatment pt will have elevated prolactin levels (because of low DA)
Phenylketonuria
Findings
Treatment
Screening
Mental Retardation, Growth Retardation, Seizures, Fair Skin, Eczema, Musty Body Odor
Treat with ↓ Phe (contained in aspartame) and ↑ Tyr in d...
Phenylketones
Phenylacetate, Phenyllactate, Phenylpyruvate
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| Term | Definition |
|---|---|
Tetrahydrobiopterin Names What replenishes it? | THB or BH4 | DHB + NADPH --> [Dihydropteridine Reductase] --> THB + NADP |
Breakdown of Catecholamines Enzymes Products | MAO and COMT DA --> HVA NE --> NorMetanephrine --> VMA Epi --> Metanephrine --> VMA |
Phenylketonuria Mutation Consequences Re AAs What builds up? Inheritance | Mutation in Phe Hydroxylase Tyr becomes essential Phe builds up leading to excess phenylketones in urine Autosomal Recessive |
Malignant Phenylketonuria What causes it? Findings | Decreased THB | PKU symptoms, but after treatment pt will have elevated prolactin levels (because of low DA) |
Phenylketonuria Findings Treatment Screening | Mental Retardation, Growth Retardation, Seizures, Fair Skin, Eczema, Musty Body Odor Treat with ↓ Phe (contained in aspartame) and ↑ Tyr in diet Screened 2-3 days after birth (normal at birth because of maternal enzyme) |
Phenylketones | Phenylacetate, Phenyllactate, Phenylpyruvate |
Maternal PKU Cause Findings | Lack of proper dietary therapy during pregnancy | Microcephaly, Mental retardation, Growth retardation, Congenital heart defects |
Alkaptonuria AKA Mutation Inheritance Danger? Findings | Ochronosis Deficiency of Homogentisic Acid Oxidase in the degradative pathway of Tyr to Fumarate AR and Benign Dark connective tissue, Brown pigmented sclera, Urine turns black on prolonged exposure to air, Debilitating arthralgias (homogentisic acid is toxic to cartilage |
Albinism Defect Inheritance Risk | Defective Tyrosinase which converts Tyr --> Melanin. AR Defective Tyr transporter (low amounts of Tyr and thus melanin) Lack of migration of Neural Crest Cells Variable inheritance Risk of Skin Cancer |
Inheritance of ocular albinism | X linked recessive |
Homocystinuria Inheritance Cause w/ Treatment | AR Cystathionine Synthase Deficiency. ↓ Met and ↑ Cys, B12, and Folate in diet ↓ affinity of cystathionine synthase for B6 (Pyridoxal Phosphate). ↑ B6 in diet Homocysteine Methyltransferase Deficiency |
Homocysteine Pathways | Homocysteine --> [Homocysteine Methyltransferase w/ B12] --> Methionine Homocysteine + Serine --> [Cystathionine Synthase w/ B6] --> Cystathionine --> Cysteine |
Homocystinuria What builds up? What happens Re AAs? Findings Test | Homocysteine builds up Cysteine becomes essential Homocysteine in urine, Mental Retardation, Osteoporosis, Tall stature, Kyphosis, Lens Subluxation (downward and inward), and atherosclerosis (Stroke and MI) Nitroprusside Cyanide Test |
Cystinuria PathoPhys Findings Inheritance Treatment | Defect of renal tubular AA transporter for cysteine, ornithine, lysine, and arginine in PCT of kidney Cystine in urine --> Precipitation of hexagonal crystals and renal staghorn calculi AR Hydration and Urinary Alkalinization |
What is Cystine | 2 cysteines connected by a disulfide bond |
Maple Syrup Urine Disease PathoPhys Findings What does it lead to? Inheritance | "I Love Vermont Maple Syrup from trees with Branches" ↓ in α-ketoacid dehydrogenase (B1) --> Blocked degradation of branched AA (Ile, Leu, Val) ↑ α-ketoacid in blood (especially Leu), Urine smells like maple syrup (burned sugar) CNS defects, Mental Retardation, Death AR |
Hartnup Disease Inheritance PathoPhys Presentation | AR Defective Neutral AA transporter on renal and intestinal epithelial cells Trp excretion in urine and ↓ absorption in gut --> pellagra |
Glucagon/Epi Pathway | Glucagon/Epi --> AC --> cAMP --> PKA --> Glycogen Phosphorylase Kinase --> Glycogen Phosphorylase --> Glycogenolysis |
Insulin Pathway | Insulin --> RTK --> Protein Phosphatase --/ Glycogen Phosphorylase Kinase and Glycogen Phosphorylase |
Glycogen Branch points Linkages | α(1,6) Branches | α(1,4) Linkages |
Fate of Glycogen in Skeletal Muscle | What regulate Glycogenonlysis during exercise? | Undergoes Glycogenolysis --> G1P --> G6P which is rapidly metabolized during exercise Ca --> glycogenolysis |
Glycogen in Hepatocytes | Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels |
Debranching Enzyme Type III | Acts on Limit Dextrin (4 glucose residues in branched configuration) to produce Glucose |
How is Glycogen degraded in lysosomes? | α-1,4-glucosidase |
Glycogen Storage Disorders Names What do they result in? | "Very Poor Carb Metabolism" Von Gierke's, Pompe's, Cori's, McArdle's Accumulation of glycogen within cells |
von Gierke's Disease Type Deficient enzyme Findings Inheritance | Type I G6Pase Fasting hypoglycemia, ↑ glycogen in liver, ↑ lactate in blood, hepatomegaly AR |
Pompe's Disease Type Deficient enzyme Findings Inheritance | "Pompe trashes the Pump" Type II Lysosomal α-1,4-glucosidase (acid maltase) Cardiomegaly and systemic findings leading to early death (Liver, Muscle) AR |
Cori's Disease Type Deficient enzyme Findings Inheritance | Type III Debranching Enzyme (α-1,6-glucosidase Milder form of type I with normal blood lactate levels. Gluconeogenesis intact AR |
McArdle's Disease Type Deficient enzyme Findings Inheritance | McArdle's = Muscles Type V Skeletal muscle glycogen phosphorylase ↑ glycogen in muscle that cannot be broken down leading to painful muscle cramps, myoglobinuria with strenuous exercise AR |
Fabry's Disease Kind of disease Deficiency What accumulates Findings Inheritance | Sphingolipidoses Lysosomal Storage Disease α-galactosidase A Ceramide Trihexoside accumulates Peripheral neuropathy of hands/feet, angiokeratomas, CV/Renal disease XR |
Gaucher's Disease Kind of disease Deficiency What accumulates Frequency Findings Histo Inheritance | Sphingolipidoses Lysosomal Storage Disease Glucocerebrosidase Glucocerebroside Most common Hepatosplenomegaly, Aseptic necrosis of femur, Bone crises, Pancytopenia, Thrombocytopenia Gaucher's cells (macs that look like crumpled tissue paper) AR. More common in Ashkenazi Jews |
Niemann-Pick Disease Kind of disease Deficiency What accumulates Findings Histo Inheritance | "No man picks his nose with his SPHINGer" Sphingolipidoses Lysosomal Storage Disease Sphingomyelinase Sphingomyelin Progressive neurodegeneration, Hepatosplenomegaly, Cherry-red spots on macula Foam cells AR. More common in Ashkenazi Jews |
Tay-Sachs Disease Kind of disease Deficiency What accumulates Findings Histo Inheritance | "Tay-SaX lacks heXosaminidase" Sphingolipidoses Lysosomal Storage Disease Hexosaminidase A GM2 Ganglioside Progressive neurodegeneration, Developmental delay, Cherry-red spots on macula, No hepatosplenomegaly Lysosomes with onion skin AR. More common in Ashkenazi Jews |
Krabbe's Disease Kind of disease Deficiency What accumulates Findings Histo Inheritance ``` | Sphingolipidoses Lysosomal Storage Disease Galactocerebrosidase Galactocerebroside Peripheral neuropathy, Developmental delay, Optic atrophy Globoid cells AR |
Metachromatic Leukodystrophy Kind of disease Deficiency What accumulates Findings Inheritance ``` | Sphingolipidoses Lysosomal Storage Disease Arylsulfatase A Cerebroside Sulfate Central and peripheral demyelination with ataxia, dementia AR |
Hurler's Syndrome Kind of disease Deficiency What accumulates Findings Inheritance ``` | Mucopolysaccharidoses Lysosomal Storage Disease α-L-iduronidase Heparan sulfate, Dermatan sulfate Developmental delay, Gargoylism, Airway obstruction, Corneal clouding, HSM AR |
Hunter's Syndrome Kind of disease Deficiency What accumulates Findings Inheritance ``` | "Hunter see clearly (no corneal clouding) and aim for the X" Mucopolysaccharidoses Lysosomal Storage Disease Iduronate Sulfatase Heparan sulfate, Dermatan sulfate Mild Hurler's + Aggressive behavior, No Corneal Clouding XR |
Lysosomal Pathways | GM2 --> [Hexosaminidase A] --> GM3 --> Glucocerebroside --> [Glucocerebrosidase] --> Ceramide Sphingomyelin --> [Sphingomyelinase] --> Ceramide Sulfatides --> [Arylsulfatase A] --> Galactocerbroside --> [Galactocerebrosidase] --> Ceramide |
Where does Fatty Acid degradation occur? | In Mitochondria |
Acyl-CoA Dehydrogenase Deficiency produces... | ↑ Dicarboxylic acids, ↓ glucose and ketones |
Carnitine Deficiency PathoPhys Presentation | Inability to transport LCFA into Mito resulting in toxic accumulation Weakness, Hypotonia, Hypoketoic hypoglycemia |
Fatty Acid Synthesis Pathway | Citrate transported out of Mito via Citrate shuttle Citrate --> [ATP citrate lyase] --> AcetylCoA AcetylCoA + CO2 (biotin) --> MalonylCoA --> Palmitate (16 carbons) |
Fatty Acid Degradation Pathway | Cytoplasm: Fatty Acid + CoA --> [FA CoA synthetase] --> Acyl-CoA Carnitine Shuttle into Mito Acyl-CoA --> β-oxidation (breakdown to AcetylCoA groups) --> Ketone Bodies or TCA Cycle |
Regulation of Carnitine Shuttle | Malonyl CoA --/ Carnitine Shuttle |
Ketone Bodies Where are they produced What are they produced from? Names? Where are they used? | Produced in liver from Fatty Acids Acetoacetate and β-hydroxybutyrate Used in muscles and brain |
Circumstances that lead to ketone body formation? PathoPhys? What are they metabolized into? What is it excreted into? | Prolonged starvation and diabetic ketoacidosis: OAA is depleted for gluconeogenesis Alcoholism: Excess NADH shunts OAA to Malate Low OAA --> stalled TCA cycle, which shunts glucose and FFA towards production of ketone bodies Metabolized into 2 molecules of AcetylCoA Excreted in urine |
Urine test for ketone bodies? | Does not detect β-hydroxybutyrate which is favored by high redox state |
Energy sources during exercise Seconds? Minutes? Hours? | Stored ATP drops. Creatinine Phosphate rises and falls Rise in Anaerobic glycolysis and Aerobic metabolism and FA oxidation with Anaerobic glycolysis larger percentage Rise in Anaerobic glycolysis and Aerobic metabolism and FA oxidation with latter having larger percentage |
Metabolism during fed state What processes? Hormones? | Glycolysis and Aerobic Respiration | Insulin stimulates storage of lipids, protein. and glycogen |
Metabolism during fasting between meals Processes Hormones | Hepatic Glycogenolysis (major), Hepatic gluconeognesis, Adipose release FFA (minor) Glucagon, Adrenaline stimulate use of fuel reserves |
Metabolism During Starvation Days 1-3 | Blood glucose levels maintained by: Hepatic glycogenolysis Adipose release FFA Muscles and Liver shift from using glucose to using FFA Hepatic gluconeogenesis from peripheral tissue lactate and Ala, and from adipose tissue glycerol and propionyl-CoA (from add chain FFA) |
How long to glycogen reserves last? | Depleted after 1 day |
Can RBC use ketone bodies? | No, they lack mito |
Metabolism of Starvation after day 3 | Adipose stores produce ketone bodies which become the main source of energy for the brain and heart. After these are depleted, protein degeneration accelerates leading to organ failure and death |
What determines survival time during starvation? | Adipose stores |
How much cholesterol is esterified? | 2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT) |
Lipid intake pathway | Chylomicrons --> [LPL] --> FFA and Chylomicron remnant FFA taken up by adipose and peripheral tissue Remnant taken up by liver via Apolipoprotein E |
Hormone Sensitive Lipase | Degrades TG stores in adipocytes |
HDL production | Liver or Intestines produce Nascent HDL Lecithin-Cholesterol Acyltransferase (LCAT) turns nascent HDL into Mature HDL by esterification of cholesterol Cholesterol Ester Transfer Protein (CETP) mediates transfer of cholesterol esters from HDL to VLDL, IDL, and LDL |
Apolipoprotein E Function What is it in? | Mediates remnant uptake | In Chylomicron, Chylomicron Remnant, VLD, IDL, and HDL. Not LDL |
Apolipoprotein A1 Function What is it in? | Activates LCAT | HDL |
Apolipoprotein C2 Function What is it in? | Lipoprotein Lipase Cofactor | Chylomicron, VLDL, HDL |
Apolipoprotein B48 Function What is it in? | Mediates Chylomicron Secretion | Chylomicron, Chylomicron remnant |
Apolipoprotein B100 Function What is it in? | Binds LDL receptor | VLDL, IDL, LDL |
What are lipoproteins composed of? | Cholesterol, TG, Phospholipids |
What lipoproteins carry most cholesterol? | LDL and HDL |
LDL Function How is it formed How is it taken up? | Delivers hepatic cholesterol to peripheral tissues Formed by hepatic lipase modification of IDL in peripheral tissue Taken up by target cells vai receptor mediated endocytosis |
HDL Function Repository for what? What secretes it? | Mediates reverse cholesterol transport from periphery to liver Acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism) Secreted from both liver and intestine |
Chylomicron Function What secretes it? | Delivers dietary TG to peripheral tissue and Delivers cholesterol to liver in the form of remnant (which is depleted of TGs) Secreted by intestinal epithelial cells |
VLDL Function What secretes it? | Delivers hepatic TG to peripheral tissue | Secreted by liver |
IDL How is it formed Function | Formed in the degradation of VLDL | Delivers TG and cholesterol to liver |
I-Hyper-Chylomicronemia Inheritance PathoPhys Blood test? Presentation | AR LPL deficiency or altered apoC2 ↑ chylomicrons, TG, cholesterol Pancreatitis, HSM, Eruptive/Pruritic Xanthomas, No ↑ risk for atherosclerosis |
IIa-Familial-HyperCholesterolemia Inheritance PathoPhys Blood test? Presentation | AD Absent of decreased LDL receptor ↑ LDL and cholesterol Accelerated atherosclerosis, Achilles tendon xanthomas, Corneal arcus |
IV HyperTriglyceridemia Inheritance PathoPhys Blood test? Presentation | AD Hepatic overproduction of VLDL ↑ VLDL and TG Pancreatitis |
Abetalipoproteinemia Inheritance PathoPhys Onset Presentation | Histo Presentation AR Defective Microsomal TG Transfer Protein (MTP) --> ↓B48 and B100 --> ↓ chylomicron and VLDL synthesis and secretion Symptoms appear in the 1st few months of life Biopsy shows lipid accumulation in enterocytes. Blood shows Acanthocytosis Failure to thrive, Steatorrhea, Ataxia, Night blindness |
What happens in Mitochondria | Fatty acid oxidation (β oxidation), Acetyl-Coa Production, TCA cycle, Oxidative Phosphorylation |
What happens metabolically in the Cytoplasm? | Glycolysis, Fatty Acid Syntesis, HMP shunt, Protein Synthesis (RER), Steroid Synthesis (SER), Cholesterol Synthesis |
What reactions occur in both the Mitochondria and the Cytoplasm? | "HUGs take 2" | Heme synthesis, Urea cycle, Gluconeogenesis |
Rate limiting step of Glycolysis | Regulators | PFK1 +: AMP, F2,6BP -: ATP, Citrate |
Rate limiting step of Gluconeognesis | Regulators | Fructose 1,6 bisphosphatase +: ATP -: AMP, F2,6BP |
Rate limiting step of TCA cycle | Regulators | Isocitrate Dehydrogenase +: ADP -: ATP, NADH |
Rate limiting step of Glycogen Synthesis | Regulators | Glycogen Synthase +: Glucose, Insulin -: Epinephrine, Glucagon |
Rate limiting step of Glycogenolysis | Regulators | Glycogen Phosphorylase +: AMP, Epinephrine, Glucagon -: Insulin, ATP |
Rate limiting step of HMP shunt | Regulators | G6PD +: NADP -: NADPH |
Rate limiting step of de novo pyrimidine synthesis | Carbamoyl Phosphate Synthetase II |
Rate limiting step of de novo purine synthesis | Regulation | Glutamine PRPP aminotransferase | Inhibited by AMP, IMP, and GMP |
Rate limiting step of urea cycle | Regulation | Carbamoyl Phosphate Synthetase I | Activated by N-acetylglutamate |
Rate limiting step of Fatty Acid Synthesis | Regulation | Acetyl-CoA Carboxylase (ACC) +: Insulin, Citrate -: Glucagon, Palmitoyl-CoA |
Rate limiting step of Fatty Acid Oxidation | Regulation | Carnitine Acyltransferase | Inhibited by Malonyl-CoA |
Rate limiting step of Ketogenesis | HMG CoA Synthase |
Rate limiting step of Cholesterol Synthesis | Regulation | HMG CoA Reductase +: Insulin, Thyroxine -: Glucagon, Cholesterol |