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).
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.
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
4
Q
Summary of pathways (100)
A
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.
- Aerobic metabolism of glucose produces…
- ATP hydrolysis
- Can be coupled to energetically unfavorable reactions.
- Arsenic
- Causes glycolysis to produce zero net ATP.
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
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
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.
- Phosphorylation of glucose to yield glucose-6-P
- 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
- Location
9
Q
Glycolysis regulation, key enzymes
- Net glycolysis
- Require ATP
- Produce ATP
A
- Net glycolysis (cytoplasm):
- Glucose + 2 Pi + 2 ADP + 2 NAD+ –> 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 (+).
- Glucose –> [Hexokinase / Glucokinase] –> Glucose-6-phosphate
- Produce ATP
- 1,3-BPG <– [Phosphoglycerate kinase] –> 3-PG
- Phosphoenolpyruvate –> [Pyruvate kinase] –> Pyruvate
- ATP (-), alanine (-), fructose-1,6-BP (+).
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 –> increased cAMP –> increased protein kinase A –> increased FBPase-2, decreased PFK-2, less glycolysis, more gluconeogenesis.
- Fed state
- Increased insulin –> decreased cAMP –> decreased protein kinase A –> decreased FBPase-2, increased PFK-2, more glycolysis, less gluconeogenesis.
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 –> acetyl-CoA + CO2 + NADH.
- The complex contains 3 enzymes that require 5 cofactors:
- Pyrophosphate (B1, thiamine; TPP)
- FAD (B2, riboflavin)
- NAD (B3, niacin)
- CoA (B5, pantothenate)
- 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 –> succinyl-CoA (TCA cycle).
- Arsenic
- Inhibits lipoic acid.
- Findings: vomiting, rice-water stools, garlic breath.
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).
13
Q
Pyruvate metabolism:
Functions of different pyruvate metabolic pathways (and their associated cofactors)
- Alanine aminotransferase
- Pyruvate carboxylase
- Pyruvate dehydrogenase
- Lactic acid dehydrogenase
A
- Alanine aminotransferase (B6):
- Alanine carries amino groups to the liver from muscle
- Pyruvate carboxylase (biotin):
- Oxaloacetate can replenish TCA cycle or be used in gluconeogenesis
- Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid):
- Transition from glycolysis to the TCA cycle
- Lactic acid dehydrogenase (B3):
- End of anaerobic glycolysis
- Major pathway in RBCs, leukocytes, kidney medulla, lens, testes, and cornea
14
Q
TCA cycle (Krebs cycle)
- Reactions
- End results
- Location
- α-ketoglutarate and pyruvate dehydrogenase complexes
A
- Reactions
- Pyruvate –> 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).
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 –> 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.
- Electron transport inhibitors
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.
- Function
- Irreversible enzymes (Pathway Produces Fresh Glucose)
-
Pyruvate carboxylase
- In mitochondria.
- Pyruvate –> oxaloacetate.
- Requires biotin, ATP.
- Activated by acetyl-CoA.
-
Phosphoenolpyruvate carboxykinase
- In cytosol.
- Oxaloacetate –> phosphoenolpyruvate.
- Requires GTP.
-
Fructose-1,6-bisphosphatase
- In cytosol.
- Fructose-1,6-BP –> fructose-6-P.
- Citrate (+), fructose 2,6-bisphosphate (-).
-
Glucose-6-phosphatase
- In ER.
- Glucose-6-P –> glucose.
-
Pyruvate carboxylase
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.
- Provides a source of NADPH from abundantly available glucose-6-P
- 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
- Oxidative (irreversible)
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 –> 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.
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.
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.
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).
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.
- Hereditary deficiency of galactokinase.
- Symptoms
- Galactose appears in blood and urine, infantile cataracts.
- May initially present as failure to track objects or to develop a social smile.
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).
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.
- An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart, called sorbitol, 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.
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)
A
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
- –> [BH4] –> Tyrosine
- 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)
A
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
- Homocysteine methyltransferase (methionine synthase) deficiency
- Treatment: increased methionine in diet
- Cystathionine synthase deficiency
- 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).
39
Q
Glycogen regulation by insulin and glucagon/epinephrine (112)
A
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 –> glucose-1-phosphate –> 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.
- Each is caused by a deficiency in one of the many lysosomal enzymes.
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
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.
- In prolonged starvation and diabetic ketoacidosis…
- 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:
- Hepatic glycogenolysis
- Adipose release of FFA
- Muscle and liver, which shift fuel use from glucose to FFA
- Hepatic 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.
- Blood glucose levels maintained by:
- 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.
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.
