SUMMARY OF PATHWAYS INHIBITORS/POISONS OF THE ETC

PATHWAY LOCATION RATE-LIMITING C NAME OF COMPLEX INHIBITORS

ENZYME I NADH Dehydrogenase Rotenone, Amobarbital
Glycolysis Cytosol PFK-1 II Succinate
Malonate (competitive)
Cytosol Dehydrogenase
Gluconeo- Fructose-1,6-
(90% Liver, III Cytochrome
genesis Bisphosphatase Antimycin A, BAL
10% Kidneys) Reductase (btc1)
Cytosol Glycogen IV Cytochrome Oxidase Cyanide (CN),
Glycogenesis
(liver & muscle) Synthase (ata3) Carbon monoxide (CO)
Cytosol Glycogen V ATP Synthase Oligomycin (direct)
Glycogenolysis
(liver & muscle) Phosphorylase ➢ NOTE: If Complex IV is inhibited, it stops the
PPP/HMPS Cytosol G6PD upstream and stops the whole ETC
Mitochondria Isocitrate ➢ UNCOUPLING AGENTS/UNCOUPLERS
Kreb’s Cycle
(matrix) Dehydrogenase - Increase permeability of inner membranes to
Mitochondria protons → Proton gradient is lost → ATP synthesis
ETC
(membrane) stops but ETC continues and substrates are still
Cytosol oxidized → ↑↑ Heat production →
[Liver (major),
Hyperthermia/Hyperpyrexia
Lactating Acetyl-CoA
FA Synthesis - Examples:
mammary Carboxylase
gland, Adipose • Aspirin
(minor)] • 2,4-Dinitrophenol
Carnitine • Thermogenin – natural uncoupling proteins
Mitochondria
FA Oxidation Acyltransferase (found in brown fat)
(matrix)
(CAT I) - Previously used for weight loss
Cytosol HMG-CoA
Mevalonate
(smooth ER) Reductase
HMG-CoA GLYCOGEN STORAGE DISEASES (GSD)
Ketogenesis Mitochondria
Lyase
T DISEASE DEFICIENCY FINDINGS
Carbamoyl
Glycogen
Phosphate 0 Hypoglycemia
Urea Cycle Liver synthase
Synthetase I
Von Glucose-6-
(CPS I) 1 Hypoglycemia
Gierke’s Phosphatase
Lysosomal
Cardiomegaly,
2 Pompe’s α-glucosidase
METABOLIC EFFECTS OF INSULIN AND GLUCAGON Heart failure
(Acid maltase)
INSULIN GLUCAGON Debranching Hypoglycemia,
3 Cori’s
Timing Fed state Fasting state enzyme Hepatomegaly
Effect ↓ Blood sugar ↑ Blood sugar Branching Hypoglycemia,
4 Andersen’s
Energy is Stored Used enzyme Hepatomegaly
Glycolysis ↑ ↓ Muscle glycogen Muscle
5 McArdle’s
Gluconeogenesis ↓ ↑ phosphorylase weakness
Glycogenesis ↑ ↓ Hepatic glycogen
6 Her’s Hypoglycemia
Glycogenolysis ↓ ↑ phosphorylase
FA Synthesis ↑ ↓ Muscle
7 Tarui’s Muscle PFK-1
FA Oxidation ↓ ↑ weakness
➢ With GLUCAGON-Like Effects:
• Epinephrine
• Cortisol
• Somatotropin

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021

 VITAMINS AND DEFICIENCY STATES LYSOSOMAL STORAGE DISORDERS (LSD)
V OTHER NAMES DEFICIENCY STATES DISORDER STATE NOTES
Night Blindness Most
Gaucher
Retinoids, (nyctalopia), β-glucosidase common
A Disease
Anti-infective Vitamin Dry eyes LSD
(xerophthalmia) Fabry
α-galactosidase
Beri-beri, Disease
Thiamine, Wernicke-Korsakoff Krabbe
B1 β-galactosidase
Aneurine (observed in alcohol Disease
intoxication) Tay Sach’s
Hexosaminidase A
Cheilosis, Disease
B2 Riboflavin
Ariboflavinosis Sandhoff’s
Hexosaminidase A & B
Niacin, Disease
Niacinamide, Farber
Pellagra (PP means Ceramidase
B3 Nicotinic Acid, Disease
pellagra-preventing)
Nicotinamide, Niemann-Pick
PP Vitamin Sphingomyelinase
Disease
Burning Foot Accumu-
B5 Pantothenic Acid Metachromatic
Syndrome Arylsulfatase A lation of
Leukodystrophy
B6 Pyridoxine Peripheral neuropathy sulfatides
Biotin, ➢ Mucopolysaccharidoses (MPS) are also LSDs
B7 Vitamin H,
Coenzyme R
Folic Acid,
Spina bifida (neural
B9 Folacin,
tube defect)
Vitamin M
B12 Cyanocobalamin Megaloblastic anemia
Ascorbic Acid,
C Scurvy
Cevitamic Acid
Cholecalciferol, Rickets,
D
Antirachitic vitamin Osteomalacia
E Tocopherols
Essential FAs
F (Linoleic acid &
Linolenic acid)
Impaired blood
Phytonadione, clotting (bleeding),
K
Phylloquinone Hemorrhagic disease
of the newborn
Permeability Factors
P
(Rutin & Hesperidin)
Ubiquinone 10,
Q10 Ubidecanenone,
Coenzyme Q10

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021

 MUCOPOLYSACCHARIDOSES (MPS)
T DISEASE ENZYMES DEFICIENT NOTES
Hurler Syndrome Most severe MPS;
(1-H) Accumulation of dermatan and heparan sulfates
Scheie Syndrome Mildest MPS;
1 α-L-iduronidase
(1-S) Accumulation of dermatan sulfate
Hurler-Scheie Intermediate in severity between 1-H & 1-S;
Syndrome (1-H/S) Accumulation of dermatan sulfate
Only type of MPS inherited as an X-linked trait;
Accumulation of heparin sulfate may occur
2 Hunter Syndrome Iduronate 2-sulfatase
2A: Neuronopathic form (severe; early progressive)
2B: Non-neuronopathic form (mild; slowly progressive)
Accumulation of heparan sulfate may occur
3-A: Heparan N-sulfatase
Sanfilippo
3 (multiple, see notes) 3-B: α-N-acetylglucosaminidase
Syndrome
3-C: Heparan-α-glucosaminide N-acetyltransferase
3-D: N-acetylglucosamine 6-sulfatase
N-acetylgalactosamine 6-sulfatase
Accumulation of keratan and chondroitin sulfates
Morquio (4-A)
4
Syndrome Accumulation of keratan sulfate;
β-galactosidase (4-B)
Milder and fewer clinical features
5 Former designation for Scheie Syndrome (1-S)
Maroteaux-Lamy
6 N-acetylgalactosamine 4-sulfatase Accumulation of dermatan sulfate
Syndrome
Accumulation of dermatan, heparan and chondroitin
7 Sly Syndrome β-glucuronidase
sulfates
With clinical and biochemical features of Morquio and
DiFerrante Sanfilippo syndromes BUT NOT A VALID MEDICAL
8 Glucosamine 6-sulfate sulfatase
Syndrome DISORDER (enzyme was normal in a patient who was
misdiagnosed)
Natowicz
9 Hyaluronidase Extremely rare
Syndrome

CONNECTIVE TISSUE DISORDERS

DISORDER STATE NOTES
Joint or skin abnormalities (due to impaired integrity);
Ehlers-Danlos Syndrome ↓ Lysyl Hydroxylase Also involves something about α-collagen-1, pro-
collagen N-peptidase (not sure if synonym?)
Excessive spinal curvature
Kyphoscoliosis ↓ Lysyl Hydroxylase*
*NOTE: Not the only cause of kyphoscoliosis
Menkes Syndrome / Kinky hair; Growth retardation;
↓ Lysyl Oxidase
Kinky Hair Syndrome Lysyl oxidase requires Cu
Kindler’s Syndrome ↓ Anchoring Fibrils Severe blistering or scarring of skin
Damage of basement
Alport’s Syndrome Hematuria
membrane of glomerulus
Marfan Syndrome Gene mutation for Fibrillin-1 Long arms, CVS risk
Genetic Emphysema /
Alpha-1 Antitrypsin ↓ α-1 Antitrypsin Causes emphysema, lung disease, and panniculitis
Deficiency (AATD)

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021

 LIPOPROTEIN METABOLISM DISORDERS
T DISORDER SYNONYMS SUB-TYPES / EXAMPLES NOTES
/ STATE
HYPOLIPOPROTEINEMIAS
Usually, mutations in
Malabsorption; Hepatic
Familial Hypo- the APOB gene (apob31,
steatosis (fatty liver) which may
β-Lipoproteinemia apob39, apob40,
progress to cirrhosis in severe
(FHBL) apob46, apob87,
cases
apob89, or apob90)
Mutations in the MTTP
“Bassen-Kornzweig
gene
Syndrome”
Growth delay; Malabsorption;
A-β-Lipoproteinemia Permanently low levels Hepatomegaly; Neurological
“Microsomal
(ABL) (below the 5th and neuromuscular
Triglyceride Transfer
percentile) of manifestations
Protein (MTTP)
apolipoprotein B and
Deficiency”
LDL- cholesterol
“Anderson Syndrome” Severe fat malabsorption
Chylomicron Retention associated with failure to thrive;
Mutations in the SAR1B
Disease (CMRD) “Lipid Transport Defect Slow growth; Weight gain;
of Intestine” Chronic diarrhea; Steatorrhea
Hepatosplenomegaly;
Hyperplastic yellow-orange
tonsils; Lymph node
enlargement; Peripheral
neuropathy; Deposition of
“Tangier Disease (TGD)”
cholesteryl and retinyl esters
Mutations in the ABCA1 and carotenoids in nonadipose
“Cholesterol
Familial α-Lipoprotein (9q31) gene tissues
thesaurismosis”
Deficiency /
Familial HDL Deficiency Almost complete ATP-binding cassette
“Defective ATP-binding
absence of plasma HDL transporter (ABC1) – a
Cassette Transporter A1
cholesterol efflux regulatory
(ABCA1)”
protein that is able to orient
cellular cholesterol towards the
cell surface and to facilitate its
transfer towards the core of
HDL
HYPERLIPOPROTEINEMIAS
Mutations in the LPL
and apolipoprotein
“Familial Lipoprotein
(apo) C-II genes
Lipase (LPL) Deficiency” Abdominal pain; Pancreatitis;
Familial Hyper-
1 Eruptive xanthomas;
chylomicronemia Criteria:
“Burger-Grutz Hepatosplenomegaly
Chylomicrons present,
Syndrome”
Normal or slightly ↑
VLDL (pre-β)

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021

 One of the most common
genetic diseases (affects approx.
1 in 250 individuals);
Presence of pathogenic Xanthomas (tendon xanthomas
variant in any of the usually indicate this type;
LDLR, APOB, and PCSK9 tuberous xanthoma; planar
genes (other related xanthoma in homozygotes);
genes include APOA2, Xanthelasma (more frequent in
Familial Hyper- GHR, EPHX2) this type);
“Low-density
β-Lipoproteinemia / Arcus corneae (arcus senilis)
2 Lipoprotein Receptor
Familial Hyper- General Criteria: before the age of 40 yrs. usually
(LDLR) Disorder”
cholesterolemia ↑ LDL (β) implies this type
2 Types: Heterozygous
Type IIa: (common) and Homozygous
Normal VLDL (pre-β) (rare);
Type IIb: Tx: Statins
↑ VLDL (pre-β) Non-statin Tx: Ezetimibe,
Bempedoic acid, PCSK9
inhibitors (e.g. Alirocumab,
Evolocumab)
“Floating β or Broad β
Disease” Mutations in the APOE
Xanthomas [xanthoma striata
gene
palmaris (planar xanthoma in
“Remnant Removal
the palms of the hands) is
Disease” Criterion: Presence of
Familial Dys- specific to this disease; tuberous
3 VLDL having abnormally
β-Lipoproteinemia xanthoma; tuberoeruptive
“Apolipoprotein E high cholesterol content
xanthoma];
(APOE) Deficiency” and abnormal
Xanthelasma (sometimes)
electrophoretic mobility
“Carbohydrate-induced (floating β or β-VLDL)
hyperlipemia”
Mutations in the APOA5
“Endogenous gene
Familial Hyper-
hyperlipemia”
pre-β-Lipoproteinemia /
4 Criteria: Tuberoeruptive xanthoma
Familial Hyper-
“Carbohydrate-inducible ↑ VLDL (pre-β),
triglyceridemia
hyperlipemia” No ↑ in LDL (β),
Chylomicrons absent
“Late-onset hyper- Mutations in the APOA5
Combined
chylomicronemia” gene
Hyperlipidemias /
Abdominal pain; Pancreatitis;
5 Hyperpre-β-
“Combined fat and Criteria: Eruptive xanthomas
Lipoproteinemia &
carbohydrate-induced Chylomicrons present,
Chylomicronemia
hyperlipemia” ↑ VLDL
➢ Bempedoic Acid (ETC-1002)
- Prodrug; Requires activation to its active metabolite, ESP15228, by Very Long-chain Acyl-CoA Synthetase I
(ACSLV1), an enzyme present in the liver and not in the skeletal muscle (thus, ↓ muscle-related A/E)
- MOA: Inhibits ATP-Citrate Lyase (ACL) → ↓ Conversion of mitochondrial-derived citrate to cytosolic ACL → Less
substrate for cholesterol and FA synthesis

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021

 AMINO ACID METABOLISM DISORDERS
DISORDER ENZYME DEFICIENT NOTES
Maple Syrup Urine Branched Chain Keto-acid Viscous, burnt sugar odor of urine; Mental retardation; Death
Disease (MSUD) Dehydrogenase Tx: Diet free of BCAAs (Val, Ile, Leu)
Musty odor of urine; Fair-skinned; Mental retardation
Phenylketonuria
Phenylalanine Hydroxylase Tx: Diet free of Phe, rich in Tyr
(PKU)
C/I: Aspartame
Alkaptonuria Homogentisic Acid Oxidase Dark urine coloration
Albinism Melanocyte Tyrosinase
Cystathionine Synthase or Cystathionine synthase requires B6
Homocystinuria
Methionine Synthase Methionine synthase requires B9 & B12
Any enzyme in the
Hyperammonemia ↑ NH3 = Nausea, vomiting, confusion, coma, death
Urea Cycle

NUCLEIC ACID METABOLISM DISORDERS

DISORDER STATE NOTES
Self-mutilation; Cognitive defects; HYPERuricemia
↓ Hypoxanthine Guanine
HGPRT converts Hypoxanthine to Inosine monophosphate
Lesch-Nyhan Syndrome Phosphoribosyl Transferase
(when deficient, hypoxanthine is instead converted to uric
(HGPRT)
acid by xanthine oxidase)
Severe Combined
↓ Adenosine Deaminase Immune dysfunctions
Immunodeficiency
Folates play an important role in the synthesis of DNA
Neural Tube Defects ↓ Folate derivatives
precursors in early pregnancy
Gout ↑ Urates

OTHER METABOLIC DISORDERS

DISORDER STATE NOTES
Refsum’s Disease /
↓ Phytanoyl-CoA Retinitis pigmentosa; Cerebellar ataxia; Anosmia;
Classic or Adult Refsum’s Disease /
Hydroxylase (PHYH) Ichthyosis; Deafness
Phytanic Acid Oxidase Deficiency

SOURCES: Manor Notes, MedlinePlus, NORD, Trease & Evans (16th ed.), NIH, AHA

APFZ / L-NU / BIOCHEM REVIEW NOTES / PLE 2021