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First Aid > Biochemistry - Metabolism > Flashcards

Biochemistry - Metabolism Flashcards

1
Q

Metabolism sites

  • Mitochondria
  • Cytoplasm
  • Both
A
  • Mitochondria
    • Fatty acid oxidation (β-oxidation), acetyl- CoA production, TCA cycle, oxidative phosphorylation.
  • Cytoplasm
    • Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER), cholesterol synthesis.
  • Both
    • Heme synthesis, Urea cycle, Gluconeogenesis.
    • HUGs take two (i.e., both).
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2
Q

Enzyme terminology

  • Kinase
  • Phosphorylase
  • Phosphatase
  • Dehydrogenase
  • Hydroxylase
  • Carboxylase
  • Mutase
  • Glucokinase
A
  • Kinase
    • Uses ATP to add high-energy phosphate group onto substrate (e.g., phosphofructokinase).
  • Phosphorylase
    • Adds inorganic phosphate onto substrate without using ATP (e.g., glycogen phosphorylase).
  • Phosphatase
    • Removes phosphate group from substrate (e.g., fructose-1,6-bisphosphatase).
  • Dehydrogenase
    • Catalyzes oxidation-reduction reactions (e.g., pyruvate dehydrogenase).
  • Hydroxylase
    • Adds hydroxyl group (-OH) onto substrate (e.g., tyrosine hydroxylase).
  • Carboxylase
    • Transfers CO2 groups with the help of biotin (e.g., pyruvate carboxylase).
  • Mutase
    • Relocates a functional group within a molecule (e.g., vitamin B12–dependent methylmalonyl-CoA mutase).
  • Glucokinase
    • An enzyme that catalyzes the phosphorylation of glucose using a molecule of ATP.
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3
Q

Rate-determining enzymes of metabolic processes

  • For each
    • Enzyme
      • regulators
      • regulators
  • Glycolysis
  • Gluconeogenesis
  • TCA cycle
  • Glycogenesis
  • Glycogenolysis
  • HMP shunt
  • De novo pyrimidine synthesis
  • De novo purine synthesis
  • Urea cycle
  • Fatty acid synthesis
  • Fatty acid oxidation
  • Ketogenesis
  • Cholesterol synthesis
A
  • Glycolysis
    • Phosphofructokinase-1 (PFK-1)
    • +: AMP, fructose-2,6-bisphosphate
    • -: ATP, citrate
  • Gluconeogenesis
    • Fructose-1,6-bisphosphatase
    • +: ATP, acetyl-CoA
    • -: AMP, fructose-2,6-bisphosphate
  • TCA cycle
    • Isocitrate dehydrogenase
    • +: ADP
    • -: ATP, NADH
  • Glycogenesis
    • Glycogen synthase
    • +: Glucose-6-phosphate, insulin, cortisol
    • -: Epinephrine, glucagon
  • Glycogenolysis
    • Glycogen phosphorylase
    • +: Epinephrine, glucagon, AMP
    • -: Glucose-6-phosphate, insulin, ATP
  • HMP shunt
    • Glucose-6-phosphate dehydrogenase (G6PD)
    • +: NADP+
    • -: NADPH
  • De novo pyrimidine synthesis
    • Carbamoyl phosphate synthetase II
  • De novo purine synthesis
    • Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
    • -: AMP, inosine monophosphate (IMP), GMP
  • Urea cycle
    • Carbamoyl phosphate synthetase I
    • +: N-acetylglutamate
  • Fatty acid synthesis
    • Acetyl-CoA carboxylase (ACC)
    • +: Insulin, citrate
    • -: Glucagon, palmitoyl-CoA
  • Fatty acid oxidation
    • Carnitine acyltransferase I
    • -: Malonyl-CoA
  • Ketogenesis
    • HMG-CoA synthase
  • Cholesterol synthesis
    • HMG-CoA reductase
    • +: Insulin, thyroxine
    • -: Glucagon, cholesterol
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4
Q

Summary of pathways (100)

A
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5
Q

ATP production

  • Aerobic vs. anaerobic
  • ATP hydrolysis
  • Arsenic
A
  • Aerobic vs. anaerobic
    • Aerobic metabolism of glucose produces…
      • 32 net ATP via malate-aspartate shuttle (heart and liver)
      • 30 net ATP via glycerol-3-phosphate shuttle (muscle).
    • Anaerobic glycolysis produces only 2 net ATP per glucose molecule.
  • ATP hydrolysis
    • Can be coupled to energetically unfavorable reactions.
  • Arsenic
    • Causes glycolysis to produce zero net ATP.
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6
Q

What is carried in activated forms by these carrier molecules

  • ATP
  • NADH, NADPH, FADH2
  • CoA, lipoamide
  • Biotin
  • Tetrahydrofolates
  • SAM
  • TPP
A
  • ATP
    • Phosphoryl groups
  • NADH, NADPH, FADH2
    • Electrons
  • CoA, lipoamide
    • Acyl groups
  • Biotin
    • CO2
  • Tetrahydrofolates
    • 1-carbon units
  • SAM
    • CH3 groups
  • TPP
    • Aldehydes
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7
Q

Universal electron acceptors

  • Universal electron acceptors
  • NAD+
  • NADPH
A
  • Universal electron acceptors
    • Nicotinamides (NAD+ from vitamin B3, NADP+)
    • Flavin nucleotides (FAD+ from vitamin B2).
  • NAD+
    • Generally used in catabolic processes to carry reducing equivalents away as NADH.
  • NADPH
    • Used in anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents.
    • A product of the HMP shunt.
    • Used in:
      • Anabolic processes
      • Respiratory burst
      • Cytochrome P-450 system
      • Glutathione reductase
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8
Q

Hexokinase vs. glucokinase

  • Phosphorylation of glucose
  • Low vs. high concentrations
  • Hexokinase vs. glucokinase
    • Location
    • Km
    • Vmax
    • Induced by insulin?
    • Feedback-inhibited by glucose-6-P?
    • Gene mutation associated with maturity-onset diabetes of the young (MODY)?
A
  • Phosphorylation of glucose
    • Phosphorylation of glucose to yield glucose-6-P
      • 1st step of glycolysis
      • 1st step of glycogen synthesis in the liver
    • Reaction is catalyzed by either hexokinase or glucokinase, depending on the tissue.
  • Low vs. high concentrations
    • At low glucose concentrations, hexokinase sequesters glucose in the tissue.
    • At high glucose concentrations, excess glucose is stored in the liver.
  • Hexokinase vs. glucokinase
    • Location
      • H: Most tissues, but not liver nor β cells of pancreas
      • G: Liver, β cells of pancreas
    • Km
      • H: Lower (increased affinity)
      • G: Higher (decreased affinity)
    • Vmax
      • H: Lower (decreased capacity)
      • G: Higher (increased capacity)
    • Induced by insulin?
      • H: No
      • G: Yes
    • Feedback-inhibited by glucose-6-P?
      • H: Yes
      • G: No
    • Gene mutation associated with maturity-onset diabetes of the young (MODY)?
      • H: No
      • G: Yes
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9
Q

Glycolysis regulation, key enzymes

  • Net glycolysis
  • Require ATP
  • Produce ATP
A
  • Net glycolysis (cytoplasm):
    • Glucose + 2 Pi + 2 ADP + 2 NAD+ Ž–> 2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O.
    • Equation not balanced chemically, and exact balanced equation depends on ionization state of reactants and products.
  • Require ATP
    • Glucose –> [Hexokinase / Glucokinase] –> Glucose-6-phosphate
      • Glucose-6-P (-) hexokinase.
      • Glucokinase in liver and β cells of pancreas
      • Hexokinase in all other tissues
    • Fructose-6-P –> [Phosphofructokinase-1, rate-limiting step] –> Fructose-1,6-BP
      • Fructose-6-P (-) glucokinase.
    • ATP (-), AMP (+), citrate (-), fructose-2,6-BP (+).
  • Produce ATP
    • 1,3-BPG <– [Phosphoglycerate kinase] –> 3-PG
    • Phosphoenolpyruvate –> [Pyruvate kinase] –> Pyruvate
    • ATP (-), alanine (-), fructose-1,6-BP (+).
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10
Q

Regulation by F2,6BP

  • FBPase-2 and PFK-2
  • Fasting state
  • Fed state
A
  • FBPase-2 and PFK-2
    • FBPase-2 and PFK-2 are the same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A.
  • Fasting state
    • Increased glucagon Ž–> increased cAMP Ž–> increased protein kinase A –> increased FBPase-2, decreased PFK-2, less glycolysis, more gluconeogenesis.
  • Fed state
    • Increased insulin –> decreased cAMP Ž–> decreased protein kinase A Ž–> decreased FBPase-2, increased PFK-2, more glycolysis, less gluconeogenesis.
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11
Q

Pyruvate dehydrogenase complex

  • Complex
  • Regulation
  • Reaction
  • The complex contains 3 enzymes that require 5 cofactors:
  • Activated by…
  • The complex is similar to…
  • Arsenic
A
  • Complex
    • Mitochondrial enzyme complex linking glycolysis and TCA cycle.
  • Regulation
    • Differentially regulated in fed/fasting states (active in fed state).
  • Reaction
    • Pyruvate + NAD+ + CoA Ž–> acetyl-CoA + CO2 + NADH.
  • The complex contains 3 enzymes that require 5 cofactors:
    1. Pyrophosphate (B1, thiamine; TPP)
    2. FAD (B2, riboflavin)
    3. NAD (B3, niacin)
    4. CoA (B5, pantothenate)
    5. Lipoic acid
  • Activated by exercise, which:
    • Increases NAD+/NADH ratio
    • Increases ADP
    • Increases Ca2+
  • The complex is similar to…
    • The α-ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts α-ketoglutarate –>Ž succinyl-CoA (TCA cycle).
  • Arsenic
    • Inhibits lipoic acid.
    • Findings: vomiting, rice-water stools, garlic breath.
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12
Q

Pyruvate dehydrogenase complex deficiency

  • Causes…
  • Findings
  • Treatment
A
  • Causes…
    • A buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
    • Lysine and Leucine—the onLy pureLy ketogenic amino acids.
  • Findings
    • Neurologic defects, lactic acidosis, increased serum alanine starting in infancy.
  • Treatment
    • Increased intake of ketogenic nutrients (e.g., high fat content or increased lysine and leucine).
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13
Q

Pyruvate metabolism:
Functions of different pyruvate metabolic pathways (and their associated cofactors)

  • Alanine aminotransferase
  • Pyruvate carboxylase
  • Pyruvate dehydrogenase
  • Lactic acid dehydrogenase
A
  1. Alanine aminotransferase (B6):
    • Alanine carries amino groups to the liver from muscle
  2. Pyruvate carboxylase (biotin):
    • Oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
  3. Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid):
    • Transition from glycolysis to the TCA cycle
  4. Lactic acid dehydrogenase (B3):
    • End of anaerobic glycolysis
    • Major pathway in RBCs, leukocytes, kidney medulla, lens, testes, and cornea
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14
Q

TCA cycle (Krebs cycle)

  • Reactions
  • End results
  • Location
  • α-ketoglutarate and pyruvate dehydrogenase complexes
A
  • Reactions
    • Pyruvate Ž–> acetyl-CoA produces 1 NADH, 1 CO2.
    • Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate.
      • Citrate
      • Isocitrate
      • KG
      • Succinyl-CoA
      • Succinate
      • Fumarate
      • Malate
      • Oxaloacetate
  • End results
    • The TCA cycle produces 3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl-CoA = 10 ATP/ acetyl-CoA (2× everything per glucose).
  • Location
    • TCA cycle reactions occur in the mitochondria.
  • α-ketoglutarate and pyruvate dehydrogenase complexes
    • α-ketoglutarate dehydrogenase complex requires the same cofactors as the pyruvate dehydrogenase complex (B1, B2, B3, B5, lipoic acid).
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15
Q

Electron transport chain and oxidative phosphorylation (104)

  • ETC
  • ATP produced via ATP synthase
    • 1 NADH –>
    • 1 FADH2 –>
  • Oxidative phosphorylation poisons
    • Electron transport inhibitors
    • ATP synthase inhibitors
    • Uncoupling agents 
A
  • ETC
    • NADH electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3- phosphate shuttle.
    • FADH2 electrons are transferred to complex II (at a lower energy level than NADH).
    • The passage of electrons results in the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.
  • ATP produced via ATP synthase
    • 1 NADH Ž–> 2.5 ATP
    • 1 FADH2 –> 1.5 ATP.
  • Oxidative phosphorylation poisons
    • Electron transport inhibitors
      • Directly inhibit electron transport, causing a decreased proton gradient and block of ATP synthesis.
      • Rotenone, cyanide, antimycin A, CO.
    • ATP synthase inhibitors
      • Directly inhibit mitochondrial ATP synthase, causing an increased proton gradient.
      • No ATP is produced because electron transport stops.
      • Oligomycin.
    • Uncoupling agents 
      • Increased permeability of membrane, causing a decreased proton gradient and increased O2 consumption.
      • ATP synthesis stops, but electron transport continues.
      • Produces heat.
      • 2,4-Dinitrophenol (used illicitly for weight loss), aspirin (fevers often occur after aspirin overdose), thermogenin in brown fat.
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16
Q

Gluconeogenesis and irreversible enzymes

  • Gluconeogenesis
    • Function
    • Location
    • Deficiency of the key gluconeogenic enzymes…
    • Odd- vs. even-chain fatty acids
  • Irreversible enzymes
A
  • Gluconeogenesis
    • Function
      • Serves to maintain euglycemia during fasting.
    • Location
      • Occurs primarily in liver
      • Enzymes also found in kidney, intestinal epithelium.
        • Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase.
    • Deficiency of the key gluconeogenic enzymes…
      • Causes hypoglycemia.
    • Odd- vs. even-chain fatty acids
      • Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle (as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source.
      • Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-CoA equivalents.
  • Irreversible enzymes (Pathway Produces Fresh Glucose)
    • Pyruvate carboxylase
      • In mitochondria.
      • Pyruvate –>Ž oxaloacetate.
      • Requires biotin, ATP.
      • Activated by acetyl-CoA.
    • Phosphoenolpyruvate carboxykinase
      • In cytosol.
      • Oxaloacetate –>Ž phosphoenolpyruvate.
      • Requires GTP.
    • Fructose-1,6-bisphosphatase
      • In cytosol.
      • Fructose-1,6-BP –>Ž fructose-6-P.
      • Citrate (+), fructose 2,6-bisphosphate (-).
    • Glucose-6-phosphatase
      • In ER.
      • Glucose-6-P Ž–> glucose.
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17
Q

HMP shunt (pentose phosphate pathway)

  • Function
  • Sites
  • 2 distinct phases
A
  • Function
    • Provides a source of NADPH from abundantly available glucose-6-P
      • NADPH is required for reductive reactions, e.g., glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis
    • Additionally, this pathway yields ribose for nucleotide synthesis and glycolytic intermediates.
    • No ATP is used or produced.
  • Sites
    • Lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs.
  • 2 distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm.
    • Oxidative (irreversible)
      • Glucose-6-Pi –> [Glucose-6-P dehydrogenase, rate-limiting step] –> CO2 + 2 NADPH + Ribulose-5-Pi
      • (+) NADP+, (-) NADPH
    • Nonoxidative (reversible)
      • Ribulose-5-Pi <– [Phosphopentose isomerase, transketolases] –> Ribose-6-Pi + G3P + F6P
      • Requires B1
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18
Q

Respiratory burst (oxidative burst) (105)

  • Functions
  • Chronic granulomatous disease (CGD)
  • Pyocyanin
  • Lactoferrin
A
  • Functions
    • Involves the activation of the phagocyte NADPH oxidase complex (e.g., in neutrophils, monocytes), which utilizes O2 as a substrate.
    • Plays an important role in the immune response –>Ž rapid release of reactive oxygen species (ROS).
    • Note that NADPH plays a role in both the creation and neutralization of ROS.
    • Myeloperoxidase is a blue-green heme-containing pigment that gives sputum its color.
  • Chronic granulomatous disease (CGD)
    • Phagocytes of patients with CGD can utilize H2O2 generated by invading organisms and convert it to ROS.
    • Patients are at increased risk for infection by catalase (+) species (e.g., S. aureus, Aspergillus) capable of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections.
  • Pyocyanin
    • Pyocyanin of P. aeruginosa functions to generate ROS to kill competing microbes.
  • Lactoferrin
    • A protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation.
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19
Q

Glucose-6-phosphate dehydrogenase deficiency (106)

  • Definition
  • NADPH
  • Blood smear
A
  • Definition
    • X-linked recessive disorder.
    • Most common human enzyme deficiency.
    • More prevalent among blacks. 
    • Increased malarial resistance.
  • NADPH
    • NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides.
    • Decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (e.g., fava beans, sulfonamides, primaquine, antituberculosis drugs).
    • Infection can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage).
  • Blood smear (Bite into some Heinz ketchup)
    • Heinz bodies—oxidized Hemoglobin precipitated within RBCs.
    • Bite cells—result from the phagocytic removal of Heinz bodies by splenic macrophages.
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20
Q

Essential fructosuria

  • Definition
  • Symptoms
A
  • Definition
    • Involves a defect in fructokinase.
    • Autosomal recessive.
    • A benign, asymptomatic condition, since fructose is not trapped in cells.
  • Symptoms
    • Fructose appears in blood and urine.
    • Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose metabolism.
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21
Q

Fructose intolerance

  • Definition
  • Diagnosis
  • Symptoms
  • Treatment
A
  • Definition
    • Hereditary deficiency of aldolase B.
    • Autosomal recessive.
    • Fructose-1-P accumulates, causing a decrease in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis.
    • Symptoms present following consumption of fruit, juice, or honey.
  • Diagnosis
    • Urine dipstick will be (-) (tests for glucose only)
    • Reducing sugar can be detected in the urine (nonspecific test for inborn errors of carbohydrate metabolism).
  • Symptoms
    • Hypoglycemia, jaundice, cirrhosis, vomiting.
  • Treatment
    • Decreased intake of both fructose and sucrose (glucose + fructose).
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22
Q

Galactokinase deficiency

  • Definition
  • Sympsoms
A
  • Definition
    • Hereditary deficiency of galactokinase.
      • Galactitol accumulates if galactose is present in diet.
    • Relatively mild condition.
    • Autosomal recessive.
  • Symptoms
    • Galactose appears in blood and urine, infantile cataracts.
    • May initially present as failure to track objects or to develop a social smile.
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23
Q

Classic galactosemia

  • Definition
  • Symptoms
  • Treatment
A
  • Definition
    • Absence of galactose-1-phosphate uridyltransferase.
    • Autosomal recessive.
    • Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
  • Symptoms
    • Failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability.
    • The more serious defects lead to PO43- depletion.
    • Classic galactosemia can lead to E. coli sepsis in neonates.
  • Treatment
    • Exclude galactose and lactose (galactose + glucose) from diet.
  • Fructose is to Aldolase B as Galactose is to UridylTransferase (FAB GUT).
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24
Q

Sorbitol

  • Sorbitol production
  • Aldose reductase vs. sorbitol dehydrogenase in tissues
A
  • Sorbitol production
    • An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart, called sorbitol, via aldose reductase.
      • Some tissues then convert sorbitol to fructose using sorbitol dehydrogenase;
      • Tissues with an insufficient amount of this enzyme are at risk for intracellular sorbitol accumulation, causing osmotic damage (e.g., cataracts, retinopathy, and peripheral neuropathy seen with chronic hyperglycemia in diabetes).
    • High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose reductase.
  • Aldose reductase vs. sorbitol dehydrogenase in tissues
    • Liver, ovaries, and seminal vesicles have both enzymes.
    • Schwann cells, retina, and kidneys have only aldose reductase.
      • Lens has primarily aldose reductase.
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25
Q

Lactase deficiency

  • Definition
  • Primary
  • Secondary
  • Congenital
  • Diagnosis
  • Findings
  • Treatment
A
  • Definition
    • Insufficient lactase enzyme Ž–> dietary lactose intolerance.
    • Lactase functions on the brush border to digest lactose (in human and cow milk) into glucose and galactose.
  • Primary
    • Age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent.
  • Secondary
    • Loss of brush border due to gastroenteritis (e.g., rotavirus), autoimmune disease, etc.
  • Congenital
    • Rare, due to defective gene.
  • Diagnosis
    • Stool demonstrates decreased pH and breath shows increased hydrogen content with lactose tolerance test.
    • Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
  • Findings
    • Bloating, cramps, flatulence, osmotic diarrhea.
  • Treatment
    • Avoid dairy products or add lactase pills to diet
    • Lactose-free milk.
26
Q

Amino acids

  • Form found in proteins
  • Essential
    • Definition
    • Glucogenic
    • Glucogenic/ketogenic
    • Ketogenic
  • Acidic
  • Basic
A
  • Form found in proteins
    • Only L-form amino acids are found in proteins.
  • Essential
    • All essential amino acids need to be supplied in the diet.
    • Glucogenic: methionine (Met), valine (Val), histidine (His).
    • Glucogenic/ketogenic: isoleucine (Ile), phenylalanine (Phe), threonine (Thr), tryptophan (Trp).
    • Ketogenic: leucine (Leu), lysine (Lys).
  • Acidic
    • Aspartic acid (Asp) and glutamic acid (Glu).
    • Negatively charged at body pH.
  • Basic
    • Arginine (Arg), lysine (Lys), histidine (His).
    • Arg is most basic.
    • His has no charge at body pH.
    • Arg and His are required during periods of growth.
    • Arg and Lys are increased in histones, which bind negatively charged DNA.
27
Q

Urea cycle

A
  • Amino acid catabolism results in the formation of common metabolites (e.g., pyruvate, acetyl- CoA), which serve as metabolic fuels.
  • Excess nitrogen (NH3) generated by this process is converted to urea and excreted by the kidneys.
  • Ordinarily, Careless Crappers Are Also Frivolous About Urination.
    • ​Ornithine
    • Carbamoyl phosphate
    • Citrulline
    • Aspartate
    • Argininosuccinate
    • Fumarate
    • Arginine
    • Urea
28
Q

Transport of ammonia by alanine and glutamate (109)

29
Q

Hyperammonemia

  • Definition
  • Treatment
  • Ammonia intoxication
A
  • Definition
    • Can be acquired (e.g., liver disease) or hereditary (e.g., urea cycle enzyme deficiencies).
    • Results in excess NH4+, which depletes α-ketoglutarate, leading to inhibition of TCA cycle.
  • Treatment
    • Limit protein in diet.
    • Benzoate or phenylbutyrate (both of which bind amino acid and lead to excretion) may be given to decreased ammonia levels.
    • Lactulose to acidify the GI tract and trap NH4+ for excretion.
  • Ammonia intoxication
    • Tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.
30
Q

N-acetylglutamate deficiency

A
  • Required cofactor for carbamoyl phosphate synthetase I.
    • Absence of N-acetylglutamate –>Ž hyperammonemia.
  • Presentation is identical to carbamoyl phosphate synthetase I deficiency.
    • However, increased ornithine with normal urea cycle enzymes suggests hereditary N-acetylglutamate deficiency.
31
Q

Ornithine transcarbamylase deficiency

  • Definition
  • Findings
A
  • Definition
    • Most common urea cycle disorder.
    • X-linked recessive (vs. other urea cycle enzyme deficiencies, which are autosomal recessive).
    • Interferes with the body’s ability to eliminate ammonia.
    • Often evident in the first few days of life, but may present with late onset.
    • Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).
  • Findings
    • Increased orotic acid in blood and urine, decreased BUN, symptoms of hyperammonemia.
    • No megaloblastic anemia (vs. orotic aciduria).
32
Q

Amino acid derivatives

  • Phenylalanine
  • Tryptophan
  • Histidine
  • Glycine
  • Glutamate
  • Arginine
A
  • Phenylalanine
    • –> [BH4] –> Tyrosine
      • –> Thyroxine
      • –> [BH4] –> Dopa
        • –> Melanin
        • –> [B6] –> Dopamine –> [Vitamin C] –> NE –> [SAM] –> Epi
  • Tryptophan
    • –> [B6] –> Niacin –> NAD+ / NADP+
    • –> [BH4, B6] –> Serotonin –> Melatonin
  • Histidine
    • –> [B6] –> Histamine
  • Glycine
    • –> [B6] –> Porphyrin –> Heme
  • Glutamate
    • –> [B6] –> GABA
    • –> Glutathione
  • Arginine
    • –> Creatine
    • –> Urea
    • –> [BH4] –> Nitric oxide
33
Q

Catecholamine synthesis/tyrosine catabolism (110)

34
Q

Phenylketonuria

  • Definition
  • Findings
  • Treatment
  • Maternal PKU
  • Phenylketones
A
  • Definition
    • Due to decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant PKU).
      • Tyrosine becomes essential.
      • Increased phenylalanine leads to excess phenylketones in urine.
    • Autosomal recessive.
      • Incidence ≈ 1:10,000.
    • Screened for 2–3 days after birth (normal at birth because of maternal enzyme during fetal life).
  • Findings
    • Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor.
    • Disorder of **aromatic **amino acid metabolism –>Ž musty body odor.
  • Treatment
    • Decreased phenylalanine and increased tyrosine in diet.
    • PKU patients must avoid the artificial sweetener aspartame, which contains phenylalanine.
  • Maternal PKU
    • Lack of proper dietary therapy during pregnancy.
    • Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
  • Phenylketones
    • Phenylacetate, phenyllactate, and phenylpyruvate.
35
Q

Alkaptonuria (ochronosis)

  • Definition
  • Findings
A
  • Definition
    • Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate.
    • Autosomal recessive.
    • Benign disease.
  • Findings
    • Dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air.
    • May have debilitating arthralgias (homogentisic acid toxic to cartilage).
36
Q

Homocystinuria

  • Types
  • All forms result in…
  • Findings
A
  • Types (all autosomal recessive):
    • Cystathionine synthase deficiency
      • Treatment: decrease methionine, increase cysteine, increase B12 and folate in diet
    • Decreased affinity of cystathionine synthase for pyridoxal phosphate
      • Treatment: really increased B6 and increased cysteine in diet
    • ƒƒHomocysteine methyltransferase (methionine synthase) deficiency
      • Treatment: increased methionine in diet
  • All forms result in excess homocysteine.
  • Findings
    • Really increased homocysteine in urine, intellectual disability, osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke and MI).
37
Q

Cystinuria

  • Definition
  • Diagnosis
  • Treatment
A
  • Definition
    • Hereditary defect of renal PCT and intestinal amino acid transporter for Cysteine, Ornithine, Lysine, and Arginine (COLA).
      • Cystine is made of 2 cysteines connected by a disulfide bond.
    • Excess cystine in the urine can lead to precipitation of hexagonal cystine stones.
    • Autosomal recessive.
    • Common (1:7000).
  • Diagnosis
    • Urinary cyanide-nitroprusside test is diagnostic.
  • Treatment
    • Urinary alkalinization (e.g., potassium citrate, acetazolamide) and chelating agents increase solubility of cystine stones
    • Good hydration.
38
Q

Maple syrup urine disease

  • Definition
  • Findings
  • Treatment
A
  • Definition
    • Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to decreased α-ketoacid dehydrogenase (B1).
      • I Love Vermont maple syrup from maple trees (with branches).
    • Autosomal recessive.
  • Findings
    • Causes increased α-ketoacids in the blood, especially those of leucine.
    • Causes severe CNS defects, intellectual disability, and death.
    • Urine smells like maple syrup/burnt sugar.
  • Treatment
    • Restriction of leucine, isoleucine, and valine in diet, and thiamine supplementation.
39
Q

Glycogen regulation by insulin and glucagon/epinephrine (112)

40
Q

Glycogen (113)

  • Glycogen
  • Skeletal muscle
  • Hepatocytes
A
  • Glycogen
    • Branches have α-(1,6) bonds
    • Linkages have α-(1,4) bonds.
    • A small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase).
  • Skeletal muscle
    • Glycogen undergoes glycogenolysis –>Ž glucose-1-phosphate –>Ž glucose-6-P, which is rapidly metabolized during exercise.
  • Hepatocytes
    • Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
    • Glycogen phosphorylase cleaves glucose-1-P residues off branched glycogen until four remain before a branch point.
      • Then 4-α-d-glucanotransferase (debranching enzyme [5]) moves three glucose-1-Ps from the branch to the linkage.
      • Then α-1,6-glucosidase (debranching enzyme[6]V) cleaves off the last glucose-1-P on the branch.
    • “Limit dextrin” refers to the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it.
41
Q

Glycogen vs. lysosomal storage diseases

  • Glycogen storage diseases
  • Lysosomal storage diseases
A
  • Glycogen storage diseases
    • 12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells.
    • Very Poor Carbohydrate Metabolism.
      • ​Von Gierke disease (type I)
      • Pompe disease (type II)
      • Cori disease (type III)
      • McArdle disease (type V)
  • Lysosomal storage diseases
    • Each is caused by a deficiency in one of the many lysosomal enzymes.
      • Results in an accumulation of abnormal metabolic products.
    • Increased incidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease in Ashkenazi Jews.
42
Q

Von Gierke disease

  • Type
  • Findings
  • Deficient Enzyme
  • Treatment
A
  • Type
    • Glycogen storage diseases (type I)
    • Autosomal recessive.
  • Findings
    • Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly
  • Deficient Enzyme
    • Glucose-6-phosphatase
  • Treatment
    • Frequent oral glucose/cornstarch; avoidance of fructose and galactose.
43
Q

Pompe disease

  • Type
  • Findings
  • Deficient Enzyme
  • Comments
A
  • Type
    • Glycogen storage disease (type II)
    • Autosomal recessive.
  • Findings
    • Cardiomyopathy and systemic findings leading to early death
  • Deficient Enzyme
    • Lysosomal α-1,4-glucosidase (acid maltase)
  • Comments
    • Pompe trashes the Pump (heart, liver, and muscle).
44
Q

Cori disease

  • Type
  • Findings
  • Deficient Enzyme
  • Comments
A
  • Type
    • Glycogen storage disease (type III)
    • Autosomal recessive.
  • Findings
    • Milder form of type I with normal blood lactate levels
  • Deficient Enzyme
    • Debranching enzyme (α-1,6-glucosidase)
  • Comments
    • Gluconeogenesis is intact.
45
Q

McArdle disease

  • Type
  • Findings
  • Deficient Enzyme
  • Comments
A
  • Type
    • Glycogen storage disease (type V)
    • Autosomal recessive.
  • Findings
    • Increased glycogen in muscle, but cannot break it down, leading
      to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities.
  • Deficient Enzyme
    • Skeletal muscle glycogen phosphorylase (myophosphorylase)
  • Comments
    • McArdle = Muscle.
46
Q

Fabry disease

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
  • Findings
    • Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease
  • Deficient Enzyme
    • α-galactosidase A
  • Accumulated Substrate
    • Ceramide trihexoside
  • Inheritance
    • XR
47
Q

Gaucher disease

  • Type
  • Findings
  • Treatment
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
  • Findings
    • Most common.
    • Hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells [A] (lipid-laden macrophages resembling crumpled tissue paper)
  • Treatment
    • Recombinant glucocerebrosidase.
  • Deficient Enzyme
    • Glucocerebrosidase (β-glucosidase)
  • Accumulated Substrate
    • Glucocerebroside
  • Inheritance
    • AR
48
Q

Niemann-Pick disease

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
    • No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase).
  • Findings
    • Progressive neurodegeneration, hepatosplenomegaly, “cherry-red” spot on macula, foam cells (lipidladen macrophages) [B]
  • Deficient Enzyme
    • Sphingomyelinase
  • Accumulated Substrate
    • Sphingomyelin
  • Inheritance
    • AR
49
Q

Tay-Sachs disease

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
  • Findings
    • Progressive neurodegeneration, developmental delay, “cherry-red” spot on macula [C], lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick)
  • Deficient Enzyme
    • Hexosaminidase A
    • Tay-SaX** lacks heXosaminidase.**
  • Accumulated Substrate
    • GM2 ganglioside
  • Inheritance
    • AR
50
Q

Krabbe disease

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
  • Findings
    • Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
  • Deficient Enzyme
    • Galactocerebrosidase
  • Accumulated Substrate
    • Galactocerebroside, psychosine
  • Inheritance
    • AR
51
Q

Metachromatic leukodystrophy

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: sphingolipidose
  • Findings
    • Central and peripheral demyelination with ataxia, dementia
  • Deficient Enzyme
    • Arylsulfatase A
  • Accumulated Substrate
    • Cerebroside sulfate
  • Inheritance
    • AR
52
Q

Hurler syndrome

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: mucopolysaccharidose
  • Findings
    • Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
  • Deficient Enzyme
    • α-L-iduronidase
  • Accumulated Substrate
    • Heparan sulfate, dermatan sulfate
  • Inheritance
    • AR
53
Q

Hunter syndrome

  • Type
  • Findings
  • Deficient Enzyme
  • Accumulated Substrate
  • Inheritance
A
  • Type
    • Lysosomal storage disease: mucopolysaccharidose
  • Findings
    • Mild Hurler + aggressive behavior, no corneal clouding
  • Deficient Enzyme
    • Iduronate sulfatase
  • Accumulated Substrate
    • Heparan sulfate, dermatan sulfate
  • Inheritance
    • XR
    • Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive).
54
Q

Fatty acid metabolism

  • Long-chain fatty acid degradation requires…
  • Carnitine deficiency
  • Acyl-CoA dehydrogenase deficiency
A
  • Long-chain fatty acid degradation requires…
    • Carnitine-dependent transport into the mitochondrial matrix.
    • CARnitine = CARnage of fatty acids.
  • Carnitine deficiency
    • Inability to transport LCFAs into the mitochondria, resulting in toxic accumulation.
    • Causes weakness, hypotonia, and hypoketotic hypoglycemia.
  • Acyl-CoA dehydrogenase deficiency
    • Increased dicarboxylic acids, decreased glucose and ketones.
    • Acetyl-CoA is a (+) allosteric regulator of pyruvate carboxylase in gluconeogenesis.
    • Decreased acetyl-CoA –> decreased fasting glucose.
    • ​“SYtrate” = SYnthesis.
55
Q

Ketone bodies

  • In the liver…
  • Other situations
    • In prolonged starvation and diabetic ketoacidosis…
    • In alcoholism…
    • Both processes cause…
  • Breath
  • Urine test for ketones
A
  • In the liver…
    • Fatty acids and amino acids are metabolized to acetoacetate and β-hydroxybutyrate (to be used in muscle and brain).
  • Other situations
    • In prolonged starvation and diabetic ketoacidosis…
      • Oxaloacetate is depleted for gluconeogenesis.
    • In alcoholism…
      • Excess NADH shunts oxaloacetate to malate.
    • Both processes cause…
      • A buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies.
  • Breath
    • Smells like acetone (fruity odor).
  • Urine test for ketones
    • Does not detect β-hydroxybutyrate.
56
Q

Metabolic fuel use:
Exercise

A
  • 1 g protein or carbohydrate = 4 kcal.
  • 1 g fat = 9 kcal.
  • 1 g alcohol = 7 kcal.
57
Q

Metabolic fuel use:
Fasting and starvation

  • Priorities
  • Fed state (after a meal)
  • Fasting (between meals)
  • Starvation days 1–3
  • Starvation after day 3
A
  • Priorities
    • Supply sufficient glucose to the brain and RBCs
    • Preserve protein.
  • Fed state (after a meal)
    • Glycolysis and aerobic respiration.
    • Insulin stimulates storage of lipids, proteins, glycogen.
  • Fasting (between meals)
    • Hepatic glycogenolysis (major)
    • Hepatic gluconeogenesis, adipose release of FFA (minor).
    • Glucagon, adrenaline stimulate use of fuel reserves.
  • Starvation days 1–3
    • Blood glucose levels maintained by:
      • ƒƒHepatic glycogenolysis
      • Adipose release of FFA
      • ƒƒMuscle and liver, which shift fuel use from glucose to FFA
      • ƒƒHepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl- CoA (from odd-chain FFA—the only triacylglycerol components that contribute to gluconeogenesis)
    • Glycogen reserves depleted after day 1.
    • RBCs lack mitochondria and so cannot use ketones.
  • Starvation after day 3
    • Adipose stores (ketone bodies become the main source of energy for the brain).
    • After these are depleted, vital protein degradation accelerates, leading to organ failure and death.
    • Amount of excess stores determines survival time.
58
Q

Cholesterol synthesis

A
  • Rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate.
  • 2⁄3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT).
  • Statins (e.g., lovastatin) competitively and reversibly inhibit HMG-CoA reductase.
59
Q

Lipid transport, key enzymes

  • Pancreatic lipase
  • Lipoprotein lipase (LPL)
  • Hepatic TG lipase (HL)
  • Hormone-sensitive lipase
  • LCAT
  • Cholesterol ester transfer protein (CETP)
A
  • Pancreatic lipase
    • Degradation of dietary triglycerides (TG) in small intestine.
  • Lipoprotein lipase (LPL)
    • Degradation of TG circulating in chylomicrons and VLDLs.
    • Found on vascular endothelial surface.
  • Hepatic TG lipase (HL)
    • Degradation of TG remaining in IDL.
  • Hormone-sensitive lipase
    • Degradation of TG stored in adipocytes.
  • LCAT
    • Catalyzes esterification of cholesterol.
  • Cholesterol ester transfer protein (CETP)
    • Mediates transfer of cholesterol esters to other lipoprotein particles.
60
Q

Major apolipoproteins

  • For each
    • Function
    • Chlyomicron and/or Chylomicron remnant?
    • VLDL and/or IDL and/or LDL and/or HDL?
  • E
  • A-I
  • C-II
  • B-48
  • B-100
A
  • E
    • Function: Mediates remnant uptake
    • Chylomicron & Chylomicron remnant
    • VLDL, IDL, & HDL
  • A-I
    • Function: Activates LCAT
    • Chylomicron
    • HDL
  • C-II
    • Function: Lipoprotein lipase cofactor
    • Chylomicron
    • VLDL & HDL
  • B-48
    • Function: Mediates chylomicron secretion
    • Chylomicron & Chylomicron remnant
  • B-100
    • Function: Binds LDL receptor
    • VLDL, IDL, & LDL
61
Q

Lipoprotein functions

  • Lipoproteins are composed of…
  • What carry most cholesterol
  • Chylomicron
  • VLDL
  • IDL
  • LDL
  • HDL
A
  • Lipoproteins are composed of…
    • Varying proportions of cholesterol, TGs, and phospholipids.
  • What carry most cholesterol
    • LDL and HDL carry most cholesterol.
  • Chylomicron
    • Delivers dietary TGs to peripheral tissue.
    • Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols.
    • Secreted by intestinal epithelial cells.
  • VLDL
    • Delivers hepatic TGs to peripheral tissue.
    • Secreted by liver.
  • IDL
    • Formed in the degradation of VLDL.
    • Delivers TGs and cholesterol to liver.
  • LDL
    • Delivers hepatic cholesterol from liver to peripheral tissues.
    • Formed by hepatic lipase modification of IDL in the peripheral tissue.
    • Taken up by target cells via receptor-mediated endocytosis.
    • LDL is Lousy.
  • HDL
    • 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.
    • Alcohol increases synthesis.
    • HDL is Healthy.
62
Q

Familial dyslipidemias

  • For each
    • Type
    • Increased blood level
    • Pathophysiology
  • Hyper-chylomicronemia
  • Familial hyper-cholesterolemia
  • Hyper-triglyceridemia
A
  • Hyper-chylomicronemia
    • Type I
    • Increased blood level
      • Chylomicrons, TG, cholesterol
    • Pathophysiology
      • Autosomal recessive.
      • Lipoprotein lipase deficiency or altered apolipoprotein C-II.
      • Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no  risk for atherosclerosis).
  • Familial hyper-cholesterolemia
    • Type IIa
    • Increased blood level
      • LDL, cholesterol
    • Pathophysiology
      • Autosomal dominant.
      • Absent or defective LDL receptors.
      • Heterozygotes (1:500) have cholesterol ≈ 300 mg/dL
      • Homozygotes (very rare) have cholesterol ≈ 700+ mg/dL.
      • Causes accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus.
  • Hyper-triglyceridemia
    • Type IV
    • Increased blood level
      • VLDL, TG
    • Pathophysiology
      • Autosomal dominant.
      • Hepatic overproduction of VLDL.
      • Causes pancreatitis.

First Aid (92 decks)

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