2/6/2019
Points on the Hydrophobic Amino Acids
USMLE Metabolic & Molecular
Biochemistry Handout 2019
Joshua D. Brooks
Associate Director of Pre-Clinical Academics, Kaplan Med
Instructor of Pharmacology, Biochemistry,
Behavioral Sciences, and Integrated Cases
joshua.brooks@kaplan.com
Points on the Hydrophobic Amino Acids
Phenylalanine: converted to tyrosine by phenylalanine hydroxylase,
requires THB--tetrahydrobiopterin (PATH: phenylketonuria from
defective enzyme OR missing cofactor)
Tyrosine: converted to melanin, catecholamines; also a target for
tyrosine kinases and phosphorylation (PHYSIO: Insulin and growth
factor signaling)
Tryptophan: converted to niacin, serotonin (requires THB)
(PATH: Hartnup disease – can’t reabsorb tryptophan in proximal
tubule—pellagra-like symptoms
Glycine: 33% of collagen (PHYSIO: Most common amino acid in
collagen, most commonly mutated amino acid in collagen)
Alanine: Converted in liver (by alanine transaminase and vitamin B6)
into pyruvate by transferring amino group (PATH: starvation)
Valine, Leucine, Isoleucine: Branched chain amino acids; metabolized
by branched chain keto-acid dehydrogenase (PATH: Enzyme
deficiency = maple syrup urine disease)
Proline: hydroxylated by prolyl hydroxylase; necessary for hydrogen
bonding to create triple helix (PATH: Scurvy)
Points on the Hydrophilic Amino Acids
Lysine: hydroxylated by lysyl hydroxylase; necessary for hydrogen
bonding to create triple helix (PATH: Scurvy)
Arginine: Formed during urea cycle; used to make nitric oxide
Histadine: weak base, converted to histamine (PHYSIO: can
accept/donate protons – buffer blood)
Aspartate: carries NH3 into urea cycle, converted to arginosuccinate
Glutamate: excitatory neurotransmitter, converted into inhibitory
neurotransmitter GABA
 2/6/2019

Points on the Hydrophilic Amino Acids Lineweaver-Burk Plot

Serine, threonine: Site of O-glycosylation in the Golgi, site of protein RECALL: Change Vmax = Decreased # of enzymes;
kinase activity (PKA, PKC, PKG) change enzyme number lower Vmax

Cysteine: reduced form (-SH, thiol) important for glutathione and

redox reactions; necessary for disulfide links when oxidized (-S-S-)

Methionine: Methyl (-CH3, no thiol) group used to make mRNA 5’ cap MNEMONIC:
1/Vmax = vertical intercept
and epinephrine; leaves –SH (thiol) group behind, making
homocysteine (can do redox reactions)

Asparagine: Site of N-glycosylation in the ER

Glutamine: NH3 acceptor in blood to prevent pH changes during Decrease enzymes  Decrease Vmax
protein breakdown Decrease Vmax  Increase 1/Vmax
Plot will shift upward

P. 126

Lineweaver-Burk Plot Pharmacological Antagonism

RECALL: Change Km = Mutate active site; Two types: Competitive & Non-competitive
Change affinity for substrate lower affinity (increase Km)
Competitive: Drug binds same site as hormone on same
receptor/enzyme

Noncompetitive: Drug binds different (allosteric) site on the same

receptor/enzyme
-1/Km = horizontal intercept

Decrease affinity for enzyme  Increase Km

Increase Km  Increase -1/Km
Plot will shift rightward

P. 126

Lineweaver-Burk Plots + Hormones
To biochemically increase Vmax,
• Increase # of enzymes
• Activators to turn enzyme on
Heterotrimeric G-Protein Cycle
Water-soluble hormone
GPCR
P. 137-138
To biochemically decrease Vmax,
• Decrease # of enzymes
• Inhibitors to turn enzyme off
Step 1: Hormone binds
receptor (GPCR); receptor
causes Gα subunit to exchange
GDP  GTP (G-protein).
Step 2: Gα dissociates from
heterotrimer to signal in cell.
Step 3: Gα hydrolyzes GTP
(GTPase) to turn off own
signaling.
Step 4: Gα reassociates with
heterotrimer.
2/6/2019
Biochemical Changes to Enzyme Kinetics
PFK-1 + AMP
Sigmoidal saturation
curve indicates PFK-1
cooperative kinetics
PFK-1 + ATP
(multiple binding sites
for substrate or
allosteric modulators)
Indicates a highly
regulated step in a
pathway
To biochemically decrease Km To biochemically increase Km
• Mutation increases binding • Mutation inhibits binding
• Allosteric activator opens • Allosteric inhibitor closes active
active site site
P. 127-128
Signaling Mechanisms
Gs Proteins: Gs: Stimulate
• Binding of agonists linked to Gs proteins increases cAMP.
• Such receptors include those for catecholamines (beta), dopamine (D1),
and glucagon.
Gs  Adenylyl cyclase  cAMP  PKA
24
 2/6/2019

Signaling Mechanisms Signaling Mechanisms

Gi Proteins: Gi: Inhibit Gq Proteins: Gq: “Quirky” = odd
• Binding of agonists linked to Gi proteins decreases cAMP. • Activates phospholipase C. Activation of PLC cleaves the membrane
• Such receptors include adrenoreceptors (alpha2), ACh (M2) dopamine phospholipid PIP2 to release the second messengers IP3 and DAG.
(D2), and several opioid and serotonin subtypes. • Binding of agonists linked to Gq proteins increase Ca2+ and PKC.
• Such receptors include receptors ACh (M1 and M3), norepinephrine
Gi  Adenylyl cyclase  cAMP  PKA (alpha1), angiotensin II, and vasopressin in vasculature (V1).

Gq  Phospholipase C  IP3  Ca++  PKC

PIP2
 DAG
MNEMONIC: Gi-coupled receptors: MNEMONIC: Smooth muscle and Gq
If you inhibit me, I’d be MAD 2. Activity causes cells to ”Q”strict

24 24
MNEMONIC: Odd muscarinics and alpha = Gq
P. 136

Signaling Mechanisms Signaling Mechanisms: Insulin

Cyclic GMP and Nitric Oxide Signaling: NOTE:
• Nitric oxide (NO) is synthesized from arginine in endothelial cells and Cytokines,
diffuses into smooth muscle. interferons,
• NO activates soluble guanylyl cyclase which makes cGMP. and growth
hormone
activate
• Atrial naturetic factor (ANF) activates a membrane receptor guanylyl cytoplasmic
cyclase since it is water soluble; the membrane receptor then makes tyrosine
cGMP and vasodilates just like nitric oxide. kinases
(JAK) to
PKB/AKT
NO  Guanylyl cyclase  cGMP  PKG yield gene
expression
changes.
ANF When insulin signals with
no glucagon competition
25 When glucagon/insulin compete Gene expression changes
P. 141
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HY Example: Insulin vs. Glucagon in Liver Abnormal G-Protein Signals

Defect Example Disease
ADP-ribosylation:
 Cholera toxin Gsα Diarrhea of cholera
 E. coli toxin Gsα Traveler's diarrhea
 Pertussis toxin G iα Pertussis (whooping cough)

1) Which bugs? Pseudomonas, diphtheria, cholera, E. coli, pertussis

2) What was the cellular target? Pseudomonas & diphtheria: eEF2
Cholera, E. coli: Gs
Pertussis: Gi
3) What was the cellular effect?
Pseudomonas & diphtheria: Inhibition of translation
Cholera, E. coli, pertussis: Increased cAMP
HIGH YIELD: Quick in liver glucose usage (glycogen & glycolysis)
4) Where does the toxin get the ADP-ribose group? NADH
Glucagon  Gs receptor Gs  cAMP  PKA  Phosphorylate proteins
Insulin  Tyrosine kinase  IRS-1  phosphatase  dephosphorylate proteins
P. 142

Outer Rod Outer Rod Intradisk Space

Rhodopsin LIGHT
Segment Segment

α αG
γ β γtβ
Cytoplasm Gt Cytoplasm
cGMP cGMP
light Na+ light Na+
-30 dark -30 dark
Membrane Membrane
Potential - Potential -
Inner Rod 35 cell membrane Inner Rod 35 cell membrane
Segment 3 sec Segment 3 sec

In the dark, cGMP is produced. cGMP Light activates the GPCR rhodopsin, and
binds/opens a Na+ channel, partially the receptor transduces that signal to Gt
Bipolar Cell depolarizing the rod cell Bipolar Cell
Light Light
P. 155-156 P. 155-156
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Outer Rod Intradisk Space Outer Rod Intradisk Space

LIGHT LIGHT
Segment Segment

αG cGMP cGMP αG cGMP cGMP

γtβ PDE Light γtβ PDE Light
Cytoplasm Cytoplasm
5’GMP 5’GMP
(inactive) (inactive)
light Na+ light Na+
-30 light -30 light
Membrane Membrane
Potential - Potential -
Inner Rod 35 cell membrane Inner Rod 35 cell membrane
Segment 3 sec Segment 3 sec

Transducin (Gt) activates phosphodiesterase Closing the Na+ channel hyperpolarizes

that metabolizes cGMP. the rod cell (Na+ stays outside)
Bipolar Cell Lack of cGMP closes the Na channel.
+
Bipolar Cell
Light Light
P. 155-156 P. 155-156

Folic Acid and Homocysteine

Outer Rod
Rhodopsin
Segment
Dihydrofolate Reductase
Folic acid (B9) Folates (THF)
α
γ β Methionine
Cytoplasm Gt
cGMP
light Na+ Homocysteine Methyl
-30 dark Thymidine (DNA)
Transferase
Membrane Purines (DNA, RNA)
Potential - Megaloblastic Anemia
Inner Rod 35 cell membrane Homocysteinemia
Segment 3 sec “recycling”
Homocysteine
N5-Methyl-THF
When dark again, transducin (Gt) stops Cystathionine (stored, unusable)
Synthase (B6)
signaling, cGMP accumulates  Na+
Bipolar Cell channel opens again (depolarize).
Cystathionine
Light
P. 155-156
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Cobalamin and Homocysteine VOMIT Pathway

Dihydrofolate Reductase Valine, Odd chain fatty acids, Methionine, Isoleucine, Threonine
Folic acid (B9) Folates (THF)
Various pathways
Methionine
Proprionyl-CoA (3C)
Prop-CoA Carboxylase Biotin (B7)
Homocysteine Methyl
Thymidine (DNA) Accumulate in myelin
Methylmalonyl-CoA (4C) Methylmalonic Aciduria
Transferase (B12)
Purines (DNA, RNA) MNEMONIC:
Peripheral neuropathy
Myelinmalonyl-CoA MMA-CoA Mutase Cobalamin (B12)
Homocysteinemia Megaloblastic Anemia
Succinyl-CoA (4C)
Homocysteine
N5-Methyl-THF
Cystathionine (stored, unusable)
Synthase (B6) Heme Synthesis Citric Acid Cycle/
Gluconeogenesis
Cystathionine

Well-Fed: Insulin & the Liver Well-Fed: Insulin & Adipose Tissue
Lipoprotein Lipase
Bile Salts Cholesterol Fatty
Lactate FAT acids VLDL
LIVER Acetyl
Fatty Acetyl Pyruvate Glucose Glucose
acids CoA
CoA Glycerol-P
Glycerol-P Urea GLUT2 CO2
Pyruvate GLUT4
Amino acids ATP
Fat CO2 GLYCOGEN CC: Since insulin is needed Glucose Glucose
ATP to take up fatty acids, high ADIPOSE TISSUE
TG levels may indicate
VLDL (a lipoprotein) untreated diabetes
LIVER: Insulin increases glucose storage as glycogen and as fats ADIPOSE: Insulin increases fatty acid and glucose absorption
• Glucose  glycogen • Increase glucose uptake for fat storage
• Glucose  Pyruvate  Acetyl-CoA  Fatty Acids  VLDL • Increase lipoprotein lipase  increase fatty acid uptake from blood
Green: Insulin-activated processes Green: Insulin-activated processes
P. 165-166 P. 165-166 + 170 (margin)
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Well-Fed: Insulin & Skeletal Muscle Post-Absorptive: Glucagon & Adipose Tissue
Hormone-
Sensitive
Glycerol
Acetyl MUSCLE Lipase
Fatty acid
CoA Amino PROTEIN RECALL: Muscle FAT Fatty
albumins
acids acids
cells high in AMP
GLUT4 Pyruvate CO2 are burning lots of Acetyl
ATP energy  they CoA
Glucose GLYCOGEN need ATP. CO2
Glucose
ATP
PHYSIO: Muscles can increase GLUT-4 during exercise via AMP kinase ADIPOSE TISSUE
(exercise helps with hyperglycemia & diabetes!)
FAT: Increased fatty acid release into blood
MUSCLE: Insulin increases glucose absorption & storage as glycogen • Lack of insulin  fat released, not stored (no glucagon effect!)
• Increase glucose uptake for glucose storage • Hyperglycemic: Insulin inhibits HSL (store fat)
• Increased glucose  glycogen • Hypoglycemic: No insulin  no inhibition of HSL (release fat)
Green: Insulin-activated processes Green: Glucagon-related processes NONE (in adipose)
P. 165-166 P. 167-168

Post-Absorptive: Glucagon & Skeletal Muscle Post-Absorptive: Glucagon & the Liver
Lactate CORI CYCLE
Fatty acid Ketone BLOOD
bodies LIVER Glycerol-P
albumins Lactate
Glycerol
Ketone PROTEIN Fatty Acetyl Pyruvate Glucose Glucose
bodies Amino acids CoA
Fatty acids
acids MUSCLE CO2 Urea
Acetyl Glucose
CoA CO ATP Alanine
2 GLYCOGEN Ketone GLYCOGEN
ATP bodies

MUSCLE: Absorbs fatty acids/ketone bodies, uses glycogen stores Fatty acid
albumins
• Abundance of fats/ketone bodies used (no glucagon effect)
LIVER: Converts fats to energy and ketone bodies; releases glucose
• Muscle uses stored glycogen for own needs (no glucagon effect)
• Fatty acids in blood  more fatty acid oxidation
• Use of glycogen: SANS activity or exercise
• Glycogen  glucose
• Muscle releases amino acids to liver for gluconeogenesis
• More enzymes to reverse liver glycolysis (gluconeogenesis)
Green: Glucagon-related processes NONE (in muscle) Green: Glucagon-related processes
P. 167-168 P. 167-168
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GLUT-2 Activity in Pancreatic β-Cells Why PFK-2 in the Liver?

4 INSULIN RELEASE:
3 During hyperglycemia, insulin wants to increase storage in the liver
Step 1: Glucose taken in via
GLUT-2 (glucose sensor)
• In all cells, glycolysis makes ATP which would shut down PFK-1.
• In the liver, glycolysis does two things  make ATP and promote fatty
1
Step 2: ATP produced via acid synthesis.
glucose metabolism • Fructose-2,6-BP (made by PFK-2) keeps PFK-1 active even if there is ATP
• Insulin turns on PFK-2  increased glycolysis in liver
Step 3: ATP closes K+
channels, cells depolarize

Step 4: Depolarization
2 opens Ca++ channels, Ca++
enters cell, insulin released

PHARM: Sulfonylureas
PATH: Maturity-Onset Diabetes of Young (MODY) Bind and close K+ channel, β-
Mutant glucokinase  ↑ Km  ↓ affinity for glucose cells release more insulin
PHARMACOLOGY SIDE EFFECT: Thiazide diuretics
Bind and open K+ channel, β-cells release less insulin  avoid in diabetes mellitus!
P. 177, 181

Glycolysis: Create Pyruvate (Final Steps) Pyruvate Dehydrogenase

2-Phosphoglycerate TAKEAWAY: Glycolysis Glucose
Enolase • 1 glucose  2 pyruvate TAKEAWAY: PDH
• 2 net ATP generated • 1 pyruvate  1 Glycolysis (cytoplasm) NADH
• Anaerobic: 2 pyruvate  2 acetyl-CoA, 1 CO2 ATP
Phosphoenolpyruvate (PEP) Pyruvate
lactate made, 2 NAD+ • 1 NADH Insulin
ADP
F-1,6-BP • RBC: Possibly 0 net ATP made NAD (liver)
Pyruvate
Pyruvate Kinase 3 Ca2+
2 ATP Dehydrogenase
ATP 3 ATP per NADH NADH (muscle)
+O2 MITOCHONDRIA
Pyruvate (oxidative phos.) (mitochondria)
Pyruvate
NADH CO2
Lactate Dehydrogenase PDH
NAD+ -O2 or -mitochondria Acetyl-CoA Acetyl CoA
Lactate TCA (Krebs) CITRIC ACID CYCLE FATTY ACID SYNTHESIS
(mitochondria) (cytoplasm)
CO2
Fatty Acid Synthesis (LIVER) CO2 + H2O Fatty Acids
P. 178, 180, 183 P. 187-188
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The Krebs Cycle Oxidative Phosphorylation: ETC

TAKEAWAY: TCA (Krebs, Citric Acid) Low [H+] Matrix e- Cytoplasm Side
• 1 acetyl-CoA  2 CO2 H+ (Intermembrane Space)
• 1 net GTP generated
Cyto b/c1 H+ High [H+]
• 3 NADH, 1 FADH2 generated “Complex III” Antimycin
PHARM: Treating CN-Toxicity
Step 1: Trap CN- in blood
NOTE: All enzymes in matrix H+
except succinate dehydrogenase Convert Hb (Fe2+) MetHb (Fe3+) H + H+
Use: nitrites e- + H+
H+ H +
(it’s on the inner membrane)
Step 2: Detoxify CN- in blood
CN- (cyanide) SCN- (thiocyanate) H
Use: thiosulfate cyt
ETC C
PHARM: Another CN- Treatment? e-
B1 Hydroxycobalamin
B2
B3 Cyto a/a3 (Cu+)
LA O2 “Complex IV”
B5 H+ Cytochrome
Q: Only dehydrogenase that doesn’t need B3? Oxidase Fe3+ Cyanide CO
A: Succinate dehydrogenase  B2 (Complex II) H 2O
P. 193-195 P. 196-198

Inhibitors of ETC and Chemiosmosis Uncouplers of Oxidative Phosphorylation

Poison Site of Inhibition Poison Site of Inhibition
Rotenone (insecticide) Complex I Dinitrophenol, toxic dose of Transports H+ across inner mitochondrial
Barbiturates Complex I aspirin membrane, avoiding ATP synthase and losing
gradient energy as heat
Doxorubicin Coenzyme Q
Antimycin (Antimycin C) Complex III HIGH YIELD: Uncouplers
Cyanide Complex IV (specifically Fe3+) • Low ATP levels  increased need for ATP  increased O2 consumption.
Carbon monoxide (CO) Complex IV • ETC tries to create H+ gradient  uncoupler releases energy (heat)
• Decreased aerobic ATP production  only anaerobic works
Oligomycin F0 subunit of ATP synthase

HIGH YIELD: ETC Inhibitors / Chemiosmosis Inhibitors

• e- movement blocked; O2 usage goes down in cells
• NADH/FADH2 no longer donate e-  shut down TCA/PDH
• Decreased aerobic ATP production  increased lactic acid
 2/6/2019

HY Gluconeogenesis Takeaways Gluconeogenesis Vs. Glycolysis Summary

3 irreversible glycolysis enzymes: Liver, kidney (minor) Yellow circles: Gluconeogenic enzymes
• Glucokinase/hexokinase Pi ATP
• Phosphofructokinase 1 (PFK-1) Glucose-6- Glucose
phosphatase 3 irreversible Glucokinase (liver)
• Pyruvate kinase
Glucose 6-P Hexokinase (kidney)

4 irreversible gluconeogenic enzymes used to reverse glycolysis: Pi

• Pyruvate carboxylase (get pyruvate out of mitochondria) Fructose 6-P ATP
Fructose-1,6-
• Phosphoenolpyruvate carboxykinase (PEPCK) (make PEP again!) bisphosphatase 2 irreversible PFK-1
• Fructose-1,6-bisphosphatase Fructose 1,6-BP
• Glucose-6-phosphatase

Pyruvate carboxylase PEP Pyruvate

3 gluconeogenic substrates: 1 irreversible
• Glycerol (becomes glycerol-3-phosphate) Phosphoenolpyruvate Pyruvate kinase
• Alanine (becomes pyruvate) & other glycogenic amino acids carboxykinase GTP ATP
(PEPCK)
• Lactate (becomes pyruvate)
Gluconeogensis Glucagon Insulin Glycolysis
P. 112-114

Fatty Acids from Digestion Cholesterol Digestion

Used Stored and Transported
High-fat meal
Cholesterol Cholesterol Ester (CE)
Triglyceride
O

=
Bile (liver) HO R-C-O
Pancreatic lipase Chol + CE
Colipase Bile (liver)
+ Apoprotein
2-Monoglyceride Pancreatic esterase + Apoprotein

Bloodstream
+ Triglycerides Chylomicron Lymph Intestine Chol E via
2 free fatty acids Chol
Stored version Transported + thoracic
(FFA) thoracic + ACAT TG duct
version Chylomicron Lymph
duct FA
Used & absorbed version Phospholipid
Bloodstream
ACAT—converts cholesterol to cholesterol esters for easier storage

P. 226
 2/6/2019

Lipoproteins
A physical complex of lipid and protein
Important Apoproteins and Lipoproteins:
• Chylomicrons: Delivery of dietary fats (primarily triglycerides) from GI to
internal tissues
Lipoproteins
A physical complex of lipid and protein
Important Apolipoproteins and Lipoproteins:
• High density (HDL): Take cholesterol and apoproteins from periphery to
recycle; transfers cholesterol to help convert IDL to LDL

• Chylomicron remnant: Remainder of chylomicron after fatty acids have • Low density (LDL): Transports cholesterol esters for absorption in tissue
been removed by lipoprotein lipase in blood; reabsorbed/recycled by liver that express LDL receptor (no triglycerides)

• Very-low density (VLDL): Delivers triglycerides (synthesized from sugar) in

the liver to the peripheral tissues ral tissues

• Intermediate density (IDL): Remainder of VLDL after fatty acids have

been removed by lipoprotein lipase in blood; reabsorbed/recycled by liver

P. 222-223

Apoproteins Apoproteins
Proteins part of lipoprotein complex Proteins part of lipoprotein complex
Important Apolipoproteins: Important Apolipoproteins:
• ApoA-I: In HDL, activates enzyme to convert cholesterol found in • ApoB-48: made in intestine; necessary for packing & transport of
vasculature into transportable cholesterol esters (which are chylomicrons
absorbed by liver or given to LDL for tissue transport)
• ApoB-100: Made in liver; necessary for packaging & transport of VLDL

PATHOLOGY: Abetalipoproteinemia
• Defect in apoB  ↓ serum triglycerides & cholesterol (can’t absorb
from diet; can’t release from liver)
• Fatty stools, developmental defects, fat-soluble vitamin deficiencies

P. 222-223 P. 222-223
 2/6/2019

Apoproteins Apoproteins
Proteins part of lipoprotein complex Proteins part of lipoprotein complex
Important Apolipoproteins: Important Apolipoproteins:
• Apo-CII: Activates lipoprotein lipase for removal and absorption of fatty • Apo-E: Binds to receptor on liver to allow for absorption of chylomicron
acids from triglycerides on chylomicrons and VLDL remnants and IDL
PATHOLOGY: Type I Hyperlipidemia PATHOLOGY: Type III Hyperlipidemia (Dysbetalipoproteinemia)
• Defect in ApoCII or lipoprotein lipase  can’t cut fat from chylomicrons • Mutant version of ApoE
• ↑ triglycerides; ↑ chylomicrons) • Can’t bind recycle receptor on liver; remnants can’t be reabsorbed/recycled
• Xanthomas • ↑ triglycerides; ↑ cholesterol; ↑ IDL, chylomicron remnants
• Fatty liver (too much fat storage) • Tuberoeruptive and palmar xanthomas
• Acute pancreatitis (elevated TGs)
• Abdominal pain after a fatty meal MNEMONIC: Remember the Apoproteins of VLDL/chylomicrons
• First, lipoprotein is Born (ApoB)
• Then, must Cut fatty acids from lipoprotein (ApoC)
• Finally, must rEcycle the rEmainder (ApoE)

P. 229, 235 P. 229

Types of Hyperlipidemias Types of Hyperlipidemias

Type Deficiency Lipid Elevated in Lipoprotein Comments Type Deficiency Lipid Elevated in Lipoprotein Comments
Blood Elevated in Blood Blood Elevated in Blood
I Hyperchylo- Triglycerides Chylomicrons Pancreatitis, red- IIa Familial hyper- Cholesterol LDL High risk of
micronemia (Ia) orange eruptive cholesterolemia atherosclerosis &
xanthomas, fatty coronary artery
Deficiency in LPL liver, abdominal Deficiency in LDL disease, xanthomas
or ApoCII (Ib) pain after fatty receptor (Apo- of Achilles tendon,
meal, creamy top B100 receptor) tuberous
Autosomal layer of serum xanthomas on
recessive Autosomal elbows, corneal
No increase in dominant arcus
atherosclerosis Heterozygote:
risk cholesterol ~ 300
mg/dL;
homozygote:
cholesterol ~ 700
mg/dL

P. 234-235 P. 234, 236

 2/6/2019

Types of Hyperlipidemias Ketone Body Metabolism

Type Deficiency Lipid Elevated in Lipoprotein Comments Acetoacetate 3-Hydroxybutyrate Blood
Blood Elevated in Blood
III Defect in ApoE Triglycerides, IDL Tuboerupitive and Cytoplasm PATH: Diabetic Ketoacidosis
synthesis cholesterol palmar • No insulin  no HSL inhibition
(mutation makes xanthomas, Mitochondrial • Excess fatty acid release
ApoE2 instead of increased risk of Matrix • Excessive ketone body
ApoE) atherosclerosis production
and coronary Acetoacetate 3-Hydroxybutyrate • Polyuria, dehydration, thirst
“remnant removal heart disease (excess ketone, hyperglycemia)
Activation of NADH NAD
+
diseases” • Decreased pH of blood
acetoacetate in Thiophorase (deplete bicarbonate)
extrahepatic (absent in liver) • Acetone breath (fruity)
tissues
PATH: Alcoholic Ketoacidosis
Acetoacetyl-CoA • Excessive ketone production
due to hypoglycemia
OAA • Even higher levels of β-
2 Acetyl-CoA Citric Acid Cycle hydroxybutyrate possible (too
much NADH)
Extrahepatic Cells

Sphingolipid Metabolism Pathology Protein Digestion

Disease Lysosomal Enzyme Substrate Symptoms Protein
Missing Accumulating in
pH (parietal cells)
Inclusion Body Pepsin Pepsinogen (chief cells)
Fabry α-galactosidase Ceramide trihexoside • Burning sensations in Intestinal lumen
hands (worse with exercise HCO3-
and hot weather)
• Angiokeratomas Active proteases Zymogens
• Cloudiness of cornea,
• Enlarged heart & kidneys, Na / aa symporter
• Cause of death usually
renal failure; Intestinal mucosa
• X-linked recessive PATHOLOGY: Hartnup Disease
PATHOLOGY: Sphingolipidosis • Defective transport of neutral amino acids  neutral amino acids stay in urine,
gut  ↓ tryptophan absorbed (and possible ↓ niacin)
Inability of lysosome to break down one particular sphingolipid substrate
 Accumulation of a single type of inclusion body in the lysosome PATHOLOGY: Cystinuria
• Defect transport in intestine and kidney of basic amino acids
PATHOLOGY: I-cell Disease (aka Inclusion cell disease)
• Cysteine not reabsorbed; may form cystine (insoluble in urine)
Golgi lacks phosphotransferase; cannot target any enzyme to lysosome  • Accumulation of renal stones
accumulation of multiple types of inclusion bodies in the lysosome
P. 255 P. 261-263
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General Nitrogen Metabolism: Liver Clinical Correlate: Elevated Homocysteine

Amino acids carbon skeleton + NH3 (highly toxic) Homocysteinemia is usually caused by vitamin deficiencies
Transaminases • fuel • NH3
• precursor • urea (liver) Pyridoxine (B6) Folate (B9) Cobalamin (B12)
Transaminases: Move the NH3 from amino acid from one carbon group to another • Enzyme: • Enzyme: • Enzyme:
cystathionine homocysteine homocysteine
GOAL: Get NH3 onto aspartate  get aspartate into urea cycle synthase methyl transferase methyl transferase
• Homocysteine ↑ • Homocysteine ↑ • Homocysteine ↑
• Can’t catabolize • Can’t recycle • Can’t recycle
Alanine transaminase (ALT) Aspartate transaminase (AST) methionine methionine methionine
Alanine aminotransferase (ALAT) Aspartate aminotransferase (ASAT) • Methionine ↑ • Methionine ↓ • Methionine ↓
• Sideroblastic • Megaloblastic • Megaloblastic
anemia anemia anemia
• No change in • No change in • Elevation in
methylmalonic acid methylmalonic acid methylmalonic acid
ALT AST

Alanine α-ketoglutarate Pyruvate Glutamate Glutamate Oxaloacetate α-ketoglutarate Aspartate

Protein breakdown Urea

P. 265-267

Heme Synthesis Pyrimidine Synthesis

Glycine + Succinyl CoA CYTOPLASM Carbamoyl Phosphate Aspartate Orotic
Rate-Limiting Heme Step
Synthetase 2 Acid
ALA Synthase (B6) Heme PATH: Acute Intermittent Porphyria CO2 + Glutamine Carbamoyl PRPP
• Autosomal dominant, late onset + ATP Phosphate
δ-Aminolevulinic Acid • Elevated porphobilinogen UMP Synthase
• Anxiety, confusion, paranoia OTC deficiency Carbamoyl-P (leaks out of mito)
UMP CO2
ALA Dehydratase Lead • Acute abdominal pain
• No photosensitivity PATHOLOGY:
Porphobilinogen PATHOLOGY: Distinguishing the cause of orotic aciduria Orotic aciduria
• Port-wine urine in some patients
Never give barbiturates • Megaloblastic anemia UMP Synthase
Porphobilinogen deaminase aka • • Decreased blood urea nitrogen OTC
Hydroxymethybilane synthase PREDICTING PORPHYRIA SYMPTOMS: • Hyperammonemia OTC
Look at the name of the elevated metabolite
“-porphyrin” = UV sensitivity
Hydroxymethylbilane “-ogen” = will eventually oxidize, become
colored (colorless before oxidation)
Uroporphyrinogen III
WHY NO BARBITURATES? Barbiturates induce
Synthase
CYP450s, which use heme  ↓ heme levels
Uroporphyrinogen-III  ↑ heme synthesis  SYMPTOMS

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