Biochemistry

Electron transport
chain and oxidative
phosphorylation

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ism

NADH electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3phosphate 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.
ADP + Pi
FADH2

NADH NAD

FAD

Complex I
2,3-Dinitrophenol
Aspirin overdose
H+

Complex II
(succinate
dehydrogenase)

Rotenone

ATP

/2O2 + 2H H2O
+

Mitochondrial
matrix
Inner mitochondrial
membrane

Cytochrome c

CoQ

P PROD
aT
ED
VI
uC

II

Complex III

Antimycin A

H+

Complex IV

Cyanide,
CO

H+

Complex V

Oligomycin

Intermembrane
space

H+

a aTP SYNTHaSE

1 NADH 2.5 ATP; 1 FADH2 1.5 ATP.

IVE PHOSPHORY
OXIDaT

laTION POISONS

Electron transport
inhibitors

Directly inhibit electron transport, causing a

proton gradient and block of ATP synthesis.

RotenONE: complex ONE inhibitor.

An-3-mycin (antimycin) A: complex 3
inhibitor.
CO/CN: complex 4 inhibitors (4 letters).

ATP synthase
inhibitors

Directly inhibit mitochondrial ATP synthase,

causing an proton gradient. No ATP is
produced because electron transport stops.

Oligomycin.

Uncoupling agents

permeability of membrane, causing a proton

gradient and 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.

Gluconeogenesis,
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-1,6bisphosphatase

In cytosol. Fructose-1,6-bisphosphate
fructose-6-phosphate.

Citrate , fructose 2,6-bisphosphate .

Glucose-6phosphatase

In ER. Glucose-6-phosphate glucose.

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. Even-chain fatty acids
cannot produce new glucose, since they yield only acetyl-CoA equivalents.

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HMP shunt (pentose

phosphate pathway)

Biochemistry

Provides a source of NADPH from abundantly available glucose-6-P (NADPH is required for
reductive reactions, eg, glutathione reduction inside RBCs, fatty acid and cholesterol biosynthesis).
Additionally, this pathway yields ribose for nucleotide synthesis and glycolytic intermediates. 2
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.

TIONS
REaC

Oxidative
(irreversible)

Nonoxidative
(reversible)

Glucose-6-phosphate
dehydrogenase
deficiency

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ism

NADP+
Glucose-6-Pi

Ribulose-5-Pi

PRODuCTS

NADPH

Glucose-6-P dehydrogenase
Rate-limiting step
Phosphopentose isomerase,
transketolases
Requires B1

NADPH is necessary to keep glutathione

reduced, which in turn detoxifies free radicals
and peroxides. NADPH in RBCs leads to
hemolytic anemia due to poor RBC defense
against oxidizing agents (eg, fava beans,
sulfonamides, primaquine, antituberculosis
drugs). Infection (most common cause) can
also precipitate hemolysis; inflammatory
response produces free radicals that diffuse
into RBCs, causing oxidative damage.

Ribose-5-Pi
Glyceraldehyde-3-phosphate
Fructose-6-P

X-linked recessive disorder; most common

human enzyme deficiency; more prevalent
among African Americans. malarial
resistance.
Heinz bodiesdenatured Hemoglobin
precipitates within RBCs due to oxidative
stress.
Bite cellsresult from the phagocytic removal
of Heinz bodies by splenic macrophages.
Think, Bite into some Heinz ketchup.
2 GSH
(reduced)

NADP+

Glucose-6-P

Glucose-6-P
dehydrogenase

6-phosphogluconate

CO2
2 NADPH
Ribulose-5-Pi

Glutathione
reductase

NADPH

H2O2

Glutathione
peroxidase

GSSG
(oxidized)

2H2O

Biochemistry

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ism

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Disorders of fructose metabolism

Essential fructosuria

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.

Fructose intolerance

Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates,

causing a in available phosphate, which results in inhibition of glycogenolysis and
gluconeogenesis. Symptoms present following consumption 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).
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: intake of both fructose and sucrose (glucose + fructose).
Fructose metabolism (liver)
Dihydroxyacetone-P
Fructokinase

Fructose

ATP

Fructose-1-P

Aldolase B
Glyceraldehyde

ADP

e
Trios
ATP

NADH

se

kina

Glyceraldehyde-3-P

Glycolysis

ADP

NAD+
Glycerol

Disorders of galactose metabolism

Galactokinase
deficiency

Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet.

Relatively mild condition. Autosomal recessive.
Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula).
Symptoms: galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile.

Classic galactosemia

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. Can
lead to E coli sepsis in neonates.
Treatment: exclude galactose and lactose (galactose + glucose) from diet.
Galactose metabolism

Galactose

Galactokinase
ATP

Aldose
reductase

ADP

Galactose-1-P

Uridyltransferase

UDP-Glu UDP-Gal

4-epimerase
Galactitol

Glucose-1-P

Glycolysis/glycogenesis

Fructose is to Aldolase B as Galactose is to

UridylTransferase (FAB GUT).
The more serious defects lead to PO43 depletion.

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Sorbitol

Biochemistry

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ism

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/activity of this enzyme are at risk
for 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.

Glucose

Aldose reductase

Sorbitol

NADPH

Sorbitol dehydrogenase

Fructose

NAD+

Schwann cells, retina, and kidneys have only aldose reductase. Lens has primarily aldose reductase.

Glucose

Aldose reductase

Sorbitol

NADPH

Lactase deficiency

Insufficient lactase enzyme 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 (eg, rotavirus), autoimmune disease, etc.
Congenital lactase deficiency: rare, due to defective gene.
Stool demonstrates pH and breath shows hydrogen content with lactose hydrogen breath test.
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.

FINDINGS

Bloating, cramps, flatulence, osmotic diarrhea.

MENT
TREaT

Avoid dairy products or add lactase pills to diet; lactose-free milk.

Amino acids

Only l-amino acids are found in proteins.

Essential

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.

All essential amino acids need to be supplied in

the diet.

Arg and His are required during periods of

growth. Arg and Lys are in histones, which
bind negatively charged DNA.

Biochemistry

Urea cycle

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ism

Ordinarily, Careless Crappers Are Also

Frivolous About Urination.

Amino acid catabolism results in the formation

of common metabolites (eg, pyruvate, acetylCoA), which serve as metabolic fuels. Excess
nitrogen (NH3) generated by this process is
converted to urea and excreted by the kidneys.

NH2

tran Ornit
sca hin
rba e
my

Ornithine

AMP + PPi

Argininosuccinate

Cytoplasm
(liver)
Urea

To kidney

A rg

Aspartate

ATP

nase

e
las

u cci

CO2

Mitochondria

Arg

H2O

rg

se

ini

ina

nos

NH2

Aspartate

Citrulline

2 ADP + Pi

Carbamoyl
phosphate

Urea
NH3

2 ATP

te
cina
suc se
no eta
ini ynth
s

N-acetylglutamate
(allosteric activator)

Carbamoyl
phosphate
synthetase I

CO2 + NH3

Arginine

Fumarate

Transport of ammonia by alanine and glutamate

T
AR
ST

Muscle
Amino acids
(NH3)

-Ketoglutarate

Liver
Alanine
(NH3)

y
Cahill cycle

lucose
Glucose
-Ketoacids

Glutamate (NH3)

Pyruvate

Asterixis

-Ketoglutarate

Glucos
Glucose
Cori cycle

Lactate

Hyperammonemia

Alanine
(NH3)

Can be acquired (eg, liver disease) or hereditary

(eg, urea cycle enzyme deficiencies).
Results in excess NH3, which depletes
-ketoglutarate, leading to inhibition of TCA
cycle.
Treatment: limit protein in diet.
May be given to ammonia levels:
Lactulose to acidify the GI tract and trap
NH4+ for excretion.
Rifaximin to colonic ammoniagenic
bacteria.
Benzoate, phenylacetate, or phenylbutyrate
to bind to NH4+ and lead to excretion.

Pyruvate

Glutamate (NH3)

Lactate

Urea (NH3)

FIN

ISH

Ammonia accumulationtremor (asterixis),

slurring of speech, somnolence, vomiting,
cerebral edema, blurring of vision.

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Biochemistry

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ism

N-acetylglutamate
synthase deficiency

Required cofactor for carbamoyl phosphate synthetase I. Absence of N-acetylglutamate

hyperammonemia.
Presents in neonates as poorly regulated respiration and body temperature, poor feeding,
developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate
synthetase I deficiency).

Ornithine
transcarbamylase
deficiency

Most common urea cycle disorder. X-linked recessive (vs other urea cycle enzyme deficiencies,
which are autosomal recessive). Interferes with the bodys ability to eliminate ammonia. Often
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

Phenylalanine

BH4

BH4

Niacin

B2, B6
Tryptophan

Tyrosine

Melanin

Glycine

B6

NAD+/NADP+

BH4, B6
Serotonin

Histidine

Dopa

B6
B6
B6

Histamine
Porphyrin
GABA

Glutamate
Glutathione
Creatine
Urea

Arginine
BH4

Melatonin

Nitric oxide

Heme

SAM

Vitamin C

Dopamine

NE

Epi