76 SEC TION II BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM

Electron transport NADH electrons are transferred to complex I.
chain and oxidative FADH2 electrons are transferred to complex II
phosphorylation (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 ATP production. ATP
hydrolysis can be coupled to energetically
unfavorable reactions.
Uncoupling proteins (found in brown fat, which
has more mitochondria than white fat) produce
heat by  inner mitochondrial membrane
permeability Ž  proton gradient. ATP synthesis
stops, but electron transport continues.
NADH NAD+ FADH2 FAD
1 NADH Ž 2.5 ATP; 1 FADH2 Ž 1.5 ATP
NADH electrons from glycolysis enter
mitochondria via the malate-aspartate or
glycerol-3-phosphate shuttle.
Aerobic metabolism of one glucose molecule
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.
Aspirin overdose can also cause uncoupling
of oxidative phosphorylation resulting in
hyperthermia.
ADP + Pi ATP
1/2 O2 + 2H+ H2O Mitochondrial
matrix

Inner mitochondrial
CoQ membrane
Cyto-
chrome c
Complex I Complex II Complex III Complex IV Complex V Intermembrane
(succinate space
dehydrogenase)

Uncoupling proteins Cyanide,

H+ H+ CO H+ H+
Aspirin overdose

Gluconeogenesis, All enzymes may be subject to activation by Pathway produces fresh glucose.
irreversible enzymes glucagon in fasting state.
Pyruvate carboxylase In mitochondria. Pyruvate Ž oxaloacetate. Requires biotin, ATP. Activated by acetyl-CoA.
Phosphoenolpyruvate In cytosol. Oxaloacetate Requires GTP.
carboxykinase Ž phosphoenolpyruvate (PEP).
Fructose-1,6- In cytosol. Fructose-1,6-bisphosphate Citrate ⊕, AMP ⊝, fructose 2,6-bisphosphate ⊝.
bisphosphatase 1 Ž fructose-6-phosphate.
Glucose-6- In ER. Glucose-6-phosphate Ž glucose.
phosphatase
Occurs primarily in liver; serves to maintain euglycemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
(Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase).
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 (It’s odd for fatty acids
to make glucose). Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-
CoA equivalents.
 BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM SEC TION II 77

Pentose phosphate Also called HMP shunt. Provides a source of NADPH from abundantly available glucose-6-P
pathway (NADPH is required for reductive reactions, eg, glutathione reduction inside RBCs, fatty acid
and cholesterol biosynthesis). Additionally, this pathway yields ribose for nucleotide synthesis. Two
distinct phases (oxidative and nonoxidative), both of which occur in the cytoplasm. No ATP is
used or produced.
Sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs.
REACTIONS
Oxidative NADP+ NADPH NADP+ NADPH CO2
(irreversible) Glucose-6-Pi 6-Phosphogluconate Ribulose-5-Pi
Glucose-6-P dehydrogenase

Nonoxidative Phosphopentose
isomerase
(reversible)
Fructose-6-Pi Ribose-5-Pi
Transketolase, B₁

Fructose Nucleotide
1,6-bisphosphate synthesis

DHAP Glyceraldehyde-3-Pi

Glucose-6-phosphate NADPH is necessary to keep glutathione
dehydrogenase reduced, which in turn detoxifies free radicals
deficiency and peroxides.  NADPH in RBCs leads to
hemolytic anemia due to poor RBC defense
against oxidizing agents (eg, fava beans,
sulfonamides, nitrofurantoin, primaquine).
Infection (most common cause) can also
precipitate hemolysis; inflammatory response
produces free radicals that diffuse into RBCs,
causing oxidative damage.
Glucose-6-P
X-linked recessive disorder; most common
human enzyme deficiency; more prevalent
among descendants of populations in malaria-
endemic regions (eg, sub-Saharan Africa,
Southeast Asia).
Heinz bodies—denatured globin chains
precipitate within RBCs due to oxidative stress.
Bite cells—result from the phagocytic removal
of Heinz bodies by splenic macrophages.
Think, “Bite into some Heinz ketchup.”
NADP+ 2 GSH H2O2
(reduced)

Glucose-6-P Glutathione Glutathione

dehydrogenase reductase peroxidase

6-phosphogluconolactone NADPH GSSG 2H2O

(oxidized)
78 SEC TION II BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM

Disorders of fructose metabolism

ENZYME DEFICIENCY
PATHOPHYSIOlOGY
PRESENTATION (SIGNS/SYMPTOMS)
ADDITIONAl REMARKS
TREATMENT
Essential fructosuria Hereditary fructose intolerance
Fructokinase (autosomal recessive) Aldolase B (autosomal recessive)
Fructose is not trapped into cells. Hexokinase Fructose-1-phosphate accumulates Ž  available
becomes 1° pathway for converting fructose to phosphate Ž inhibition of glycogenolysis and
fructose-6-phosphate. gluconeogenesis.
Asymptomatic, benign. Fructose appears in Hypoglycemia, jaundice, cirrhosis, vomiting.
blood and urine (fructokinase deficiency is Symptoms only present following consumption
kinder). of fruit, juice, or honey.
Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine
(nonspecific test for inborn errors of carbohydrate metabolism).
–  intake of fructose, sucrose (glucose + fructose),
and sorbitol (metabolized to fructose).
Triose phosphate
isomerase
Dihydroxyacetone-P
Fructokinase Aldolase B
Fructose Fructose-1-P se Glyceraldehyde-3-P Glycolysis
se kina
Trio
ATP ADP Glyceraldehyde
ADP
ATP
NADH

NAD+
Glycerol

Disorders of galactose metabolism

ENZYME DEFICIENCY
PATHOPHYSIOlOGY
PRESENTATION (SIGNS/SYMPTOMS)
TREATMENT
Galactokinase deficiency
Galactokinase (autosomal recessive).
Galactitol accumulates if diet has galactose.
Relatively mild/benign condition (galactokinase
deficiency is kinder).
Galactose appears in blood (galactosemia) and
urine (galactosuria); infantile cataracts. May
present as failure to track objects or develop
social smile.
– Exclude galactose and lactose (galactose +
Galactokinase
Galactose
Classic galactosemia
Galactose-1-phosphate uridyltransferase
(autosomal recessive).
Damage caused by accumulation of toxic
substances (eg, galacitol).
Symptoms start when infant is fed formula
or breast milk Ž failure to thrive, jaundice,
hepatomegaly, infantile cataracts (galacitol
deposition in eye lens), intellectual disability.
Can predispose neonates to E coli sepsis.
glucose) from diet.
Uridylyltransferase
Galactose-1-P Glucose-1-P

ATP
ADP
UDP-Glu UDP-Gal
Aldose
reductase

4-Epimerase Glycolysis/glycogenesis

Galactitol
 BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM SEC TION II 79

Sorbitol An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart,
sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using sorbitol
dehydrogenase; tissues with an insufficient amount/activity of this enzyme are at risk of
intracellular sorbitol accumulation, causing osmotic damage (eg, 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.
Liver, ovaries, and seminal vesicles have both enzymes (they lose sorbitol).
Aldose reductase Sorbitol dehydrogenase
Glucose Sorbitol Fructose
NADPH NAD+

Lens has primarily Aldose reductase. Retina, Kidneys, and Schwann cells have only aldose
reductase (LARKS).

Lactase deficiency Insufficient lactase enzyme Ž dietary lactose intolerance. Lactase functions on the intestinal brush
border to digest lactose (in milk and milk products) 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 intestinal brush border due to gastroenteritis (eg, rotavirus), autoimmune disease.
Congenital lactase deficiency: rare, due to defective gene.
Stool demonstrates  pH and breath shows  hydrogen content with lactose hydrogen breath test
(H+ is produced when colonic bacteria ferment undigested lactose). Intestinal biopsy reveals
normal mucosa in patients with hereditary lactose intolerance.
FINDINGS Bloating, cramps, flatulence (all due to fermentation of lactose by colonic bacteria Ž gas), and
osmotic diarrhea (undigested lactose).
TREATMENT Avoid dairy products or add lactase pills to diet; lactose-free milk.

Amino acids Only l-amino acids are found in proteins.

Essential PVT TIM HaLL: Phenylalanine, Valine, Tryptophan, Threonine, Isoleucine, Methionine,
Histidine, Leucine, Lysine.
Glucogenic: Methionine, histidine, valine. We met his valentine, who is so sweet (glucogenic).
Glucogenic/ketogenic: Isoleucine, phenylalanine, threonine, tryptophan.
Ketogenic: leucine, lysine. The only purely ketogenic amino acids.
Acidic Aspartic acid, glutamic acid.
Negatively charged at body pH.
Basic Arginine, histidine, lysine.
Arginine is most basic. Histidine has no charge at body pH.
Arginine and histidine are required during periods of growth.
Arginine and lysine are  in histones which bind negatively charged DNA.
His lys (lies) are basic.
80 SEC TION II BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM

Urea cycle Amino acid catabolism generates common Ordinarily, Careless Crappers Are Also
metabolites (eg, pyruvate, acetyl-CoA), which Frivolous About Urination.
serve as metabolic fuels. Excess nitrogen is
converted to urea and excreted by the kidneys.
CO2 + H2O

HCO3– + NH3
2 ATP Aspartate
Carbamoyl Citrulline
N-acetylglutamate phosphate
2 ADP + Pi
synthetase I Arg
(allosteric activator) e
las

rba e

ini ynth
sca hin
ATP

my

no eta
s
tran Ornit

suc se
Carbamoyl

cina
Urea phosphate AMP + PPi

te
NH3 NH2 Mitochondria
Ornithine Argininosuccinate
CO2 C O

lya s c c i n a t e
Cytoplasm
(liver)
Aspartate NH2

e
u
nos
A rg
To kidney Urea

ini
ina

rg
se
A
H 2O
Arginine
Fumarate

Transport of ammonia by alanine

Muscle Liver
START
Amino acids Alanine Alanine
(NH3) α-Ketoglutarate (NH3) (NH3) α-Ketoglutarate
Cahill cycle
y
lucose
Glucose Glucos
Glucose

α-Ketoacids Glutamate (NH3) Pyruvate Cori cycle Pyruvate Glutamate (NH3)

Lactate Lactate Urea (NH3) FINISH

Hyperammonemia Can be acquired (eg, liver disease) or hereditary Treatment: limit protein in diet.
(eg, urea cycle enzyme deficiencies). May be given to  ammonia levels:
Presents with flapping tremor (asterixis), slurring ƒ Lactulose to acidify GI tract and trap NH4+
of speech, somnolence, vomiting, cerebral for excretion.
edema, blurring of vision. ƒ Antibiotics (eg, rifaximin) to
 NH3 changes relative amounts of  ammoniagenic bacteria.
α-ketoglutarate, glutamate, GABA, and ƒ Benzoate, phenylacetate, or phenylbutyrate
Asterixis
glutamine. CNS toxicity mainly involves: react with glycine or glutamine, forming
ƒ  GABAergic tone ( GABA) products that are excreted renally.
ƒ TCA cycle inhibition ( α-ketoglutarate)
NH3 NH3
ƒ Cerebral edema (glutamine induced osmotic
shifts) -ketoglutarate Glutamate Glutamine
B6
GABA
 BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM SEC TION II 81

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

Amino acid derivatives Thyroxine Melanin

BH4 BH4 B6 Vitamin C SAM

Phenylalanine Tyrosine Dopa Dopamine NE Epi

B2, B6 Niacin NAD+/NADP+

Tryptophan BH4, B6
Serotonin Melatonin
B6
Histidine Histamine
B6
Glycine Porphyrin Heme

B6 GABA
Glutamate
B6
Glutathione

Creatine
Arginine Urea

BH4 Nitric oxide

BH4 = tetrahydrobiopterin

Catecholamine synthesis/tyrosine catabolism

Phenylalanine
Phenylalanine
BH4 PKU
hydroxylase

Homogentisic acid Tyrosine

BH4 Tyrosine
Alkaptonuria Homogentisate hydroxylase Albinism
oxidase
DOPA Tyrosinase
Maleylacetoacetic acid (Dihydroxyphenylalanine) Melanin

Fumarate B6 DOPA – Carbidopa

decarboxylase
Dopamine

TCA cycle Vitamin C Dopamine

β-hydroxylase
Catechol-O-methyltransferase
Norepinephrine

Phenylethanolamine-N-
SAM methyltransferase Cortisol Normetanephrine
Catechol-O- Monoamine Monoamine
methyltransferase oxidase oxidase
Epinephrine Metanephrine Vanillylmandelic acid Homovanillic acid
84 SEC TION II BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM

Glycogen regulation by insulin and glucagon/epinephrine

Epinephrine Epinephrine
(liver and muscle) (liver)
Insulin
(liver and muscle)
Glucagon Receptor Receptor
(liver) Tyrosine
te kinase
Adenyla
c y c la s e dimer
receptor
Glucagon Endoplasmic
receptor cAMP Calcium-calmodulin
ATP in muscle during reticulum
contraction
Protein kinase A Calcium
Protein kinase A
Glycogen
−
Glycogen
phosphorylase kinase
Glycogen Glycogen
phosphorylase synthase
−

Protein phosphatase
Glucose

Glycogen Branches have α-(1,6) bonds; linear linkages have α-(1,4) bonds.
Skeletal muscle Glycogen undergoes glycogenolysis Ž glucose-1-phosphate Ž glucose-6-phosphate, which is
rapidly metabolized during exercise.
Hepatocytes Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4
glucose units remain on a branch. Then 4-α-d-glucanotransferase (debranching enzyme ) moves
3 of the 4 glucose units from the branch to the linear linkage. Then α-1,6-glucosidase (debranching
enzyme ) cleaves off the last residue, liberating a free glucose.
Limit dextrin—2–4 residues remaining on a branch after glycogen phosphorylase has shortened it.
Glycogen storage
disease type
I Von Gierke disease
II Pompe disease

Gluconeogenesis Glycolysis III Cori disease

Glucose IV Anderson disease

II V McArdle disease
I
Lysosome only
Glucose-6-P Glycogen enzymes
III Glucose-6-phosphatase
UDP-glucose pyrophosphorylase
Glucose-1-P
Glycogen synthase
Branching enzyme
III
UDP-glucose Glycogen phosphorylase
IV
Debranching enzyme
(4-α-D-glucanotransferase)
V Debranching enzyme
Glycogen Limit dextrin
(α-1,6-glucosidase)
Glycogenesis / glycogenolysis
α-1,4-glucosidase

Note: A small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase).

 BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM SEC TION II 85

Glycogen storage At least 15 types have been identified, all Vice president can’t accept money.
diseases resulting in abnormal glycogen metabolism Types I-V are autosomal recessive.
and an accumulation of glycogen within cells. Andersen: Branching.
Periodic acid–Schiff stain identifies glycogen Cori: Debranching. (ABCD)
and is useful in identifying these diseases.
DISEASE FINDINGS DEFICIENT ENZYME COMMENTS
Von Gierke disease Severe fasting hypoglycemia, Glucose-6-phosphatase. Treatment: frequent oral
(type I)  Glycogen in liver and glucose/cornstarch; avoidance
kidneys,  blood lactate, of fructose and galactose.
 triglycerides,  uric acid Impaired gluconeogenesis and
(Gout), and hepatomegaly, glycogenolysis.
renomegaly. Liver does not
regulate blood glucose.
Pompe disease Cardiomyopathy, hypotonia, Lysosomal acid α-1,4- Pompe trashes the pump (1st
(type II) exercise intolerance, enlarged glucosidase (acid maltase). and 4th letter; heart, liver,
tongue, and systemic findings and muscle).
lead to early death.
Cori disease Similar to von Gierke disease, Debranching enzymes Gluconeogenesis is intact.
(type III) but milder symptoms and (α-1,6-glucosidase and
normal blood lactate levels. 4-α-d-glucanotransferase).
Can lead to cardiomyopathy.
Limit dextrin–like structures
accumulate in cytosol.
Andersen disease Most commonly presents Branching enzyme. Hypoglycemia occurs late in
(type IV) with hepatosplenomegaly Neuromuscular form can the disease.
and failure to thrive in early present at any age.
infancy.
Other findings include
infantile cirrhosis, muscular
weakness, hypotonia,
cardiomyopathy early
childhood death.
McArdle disease  glycogen in muscle, but Skeletal muscle glycogen Blood glucose levels typically
(type V) muscle cannot break it down phosphorylase unaffected.
Ž painful muscle cramps, (myophosphorylase). McArdle = muscle.
myoglobinuria (red urine) Characterized by a flat venous
with strenuous exercise, and lactate curve with normal
arrhythmia from electrolyte rise in ammonia levels during
abnormalities. Second-wind exercise.
phenomenon noted during
exercise due to  muscular
blood flow.
86 SEC TION II BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM

Lysosomal storage Lysosomal enzyme deficiency Ž accumulation of abnormal metabolic products.  incidence of
diseases Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease in Ashkenazi Jews.
DISEASE FINDINGS DEFICIENT ENZYME ACCUMUlATED SUBSTRATE INHERITANCE
Sphingolipidoses
Tay-Sachs disease Progressive neurodegeneration, Hexosaminidase A GM2 ganglioside. AR
A developmental delay, hyperreflexia, (“TAy-Sax”).
hyperacusis, “cherry-red” spot on
macula A (lipid accumulation in
ganglion cell layer), lysosomes with
onion skin, no hepatosplenomegaly
(vs Niemann-Pick).
Fabry disease Early: triad of episodic peripheral α-galactosidase A. Ceramide XR
B neuropathy, angiokeratomas B , trihexoside
hypohidrosis. (globotriaosylce-
Late: progressive renal failure, ramide).
cardiovascular disease.
Metachromatic Central and peripheral demyelination Arylsulfatase A. Cerebroside sulfate. AR
leukodystrophy with ataxia, dementia.
Krabbe disease Peripheral neuropathy, destruction Galactocerebrosi- Galactocerebroside, AR
of oligodendrocytes, developmental dase (galactosylce- psychosine.
delay, CN II atrophy, globoid cells. ramidase).
Gaucher disease Most common. Glucocerebrosidase Glucocerebroside. AR
Hepatosplenomegaly, pancytopenia, (β-glucosidase); treat
osteoporosis, avascular necrosis of with recombinant
femur, bone crises, Gaucher cells glucocerebrosidase.
(lipid-laden macrophages resembling
crumpled tissue paper).
Niemann-Pick disease Progressive neurodegeneration, Sphingomyelinase. Sphingomyelin. AR
C hepatosplenomegaly, foam cells
(lipid-laden macrophages) C ,
“cherry-red” spot on macula A .

Mucopolysaccharidoses
Hurler syndrome Developmental delay, hirsutism, α-l-iduronidase. Heparan sulfate, AR
skeletal anomalies, airway obstruction, dermatan sulfate.
clouded cornea, hepatosplenomegaly.
Hunter syndrome Mild Hurler + aggressive behavior, no Iduronate-2 (two)- Heparan sulfate, XR
corneal clouding. sulfatase. dermatan sulfate.

GM2 Ceramide trihexoside Hunters see clearly (no corneal clouding) and
aggressively aim for the X (X-linked recessive).
GM3
Sulfatides
Glucocerebroside

Galactocerebroside Ceramide Sphingomyelin

 BIOCHEmISTRY ` BIOCHEMISTRY—METABOlISM SEC TION II 87

Fatty acid metabolism Fatty acid synthesis requires transport of citrate

from mitochondria to cytosol. Predominantly
Synthesis Degradation occurs in liver, lactating mammary glands, and
Fatty acid synthesis adipose tissue.
(palmitate, a 16C FA)
Long-chain fatty acid (LCFA) degradation
Fatty acid + CoA requires carnitine-dependent transport into the
Malonyl-CoA −
Fatty acyl-CoA mitochondrial matrix.
Insulin Acetyl-CoA
carboxylase synthetase
Glucagon − CO2 (biotin) “Sytrate” = synthesis.
Acetyl-CoA Fatty acyl-CoA
Carnitine Carnitine = carnage of fatty acids.
ATP citrate palmitoyl
Cytoplasm lyase transferase I Systemic 1° carnitine deficiency—no cellular
Mitochondrial Citrate Carnitine
uptake of carnitine Ž no transport of LCFAs
membranes shuttle shuttle into mitochondria Ž toxic accumulation
of LCFAs in the cytosol. Causes weakness,
Mitochondrial
matrix hypotonia, hypoketotic hypoglycemia, dilated
cardiomyopathy.
Citrate Fatty acyl-CoA
β-oxidation Medium-chain acyl-CoA dehydrogenase
(acyl-CoA
dehydrogenases) deficiency— ability to break down fatty
Acetyl-CoA
acids into acetyl-CoA Ž accumulation
of fatty acyl carnitines in the blood with
Ketone TCA
hypoketotic hypoglycemia. Causes vomiting,
bodies cycle lethargy, seizures, coma, liver dysfunction,
hyperammonemia. Can lead to sudden death
in infants or children. Treat by avoiding
fasting.