ENZYMOPATHY

- biochemical connections -
Vladimíra Kvasnicová
 Used pictures are taken
from the recommended study literature:

Lippincott Illustrated Reviews: Biochemistry

Emine E. Abali , Susan D. Cline , David S. Franklin , Susan M. Viselli Ph.D.
ISBN/ISSN: 9781975155063
Publication Date: April 12, 2021 / Edition: 8

Textbook of Biochemistry with Clinical Correlations

Thomas M. Devlin
ISBN: 978-0470281734
Publication Date: January 1, 2010 / Edition: 7
 Metabolism of aromatic amino acids
Phenylalanin
-

estrogen .

&

With NADH.

Degradation of phenylalanine and tyrosine

(also synthesis of tyrosine from
↓
phenylalanine)

BHu/FHB
Phenylketonuria
phenylalanine hydroxylase deficiency
 Tetrahydrobiopterin (THB) as a cofactor necessary for the
• degradation of phenylalanine
• synthesis of tyrosine from phenylalanine
• synthesis of catecholamines from tyrosine
(dopamine, norepinephrine, epinephrine)
• serotonin (neurotransmitter) synthesis from tryptophan

In all these cases, hyperphenylalaninemia occurs if the metabolism of THB is

disrupted. In addition, also the signaling molecules are missing.
 Tetrahydrobiopterin
• is not a vitamin derivative
• is synthesized in the body

Thomas M. Devlin: Textbook of Biochemistry with

Clinical Correlations
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 pigment melanin
Albinism
tyrosinase deficiency
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 individual intermediates
you don't have to learn

&+
e
& oxidation, the pigment
alkaptone is formed
can harmful join cartilage > a

Tyrosinemia Imovement
-
,

fumaryl acetoacetate
hydrolase deficiency
Alkaptonuria
homogentisate oxidase
deficiency
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
Metabolism of sulfur containing
amino acids

2 fates of homocysteine

1) transsulfuration
• synthesis of cysteine
2) remethylation
• restoration of methionine

Homocystinuria
cystathionine-β-synthase
deficiency
(CBS)
 Remethylation of homocysteine to methionine
• requires an enzyme whose cofactor is vitamin B12
• the methyl group donor is methyl-THF, or alternatively betaine
(= N,N,N-trimethylglycine)

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 C1-fragments

• formyl (-CHO)

Cofactor THF
(tetrahydrofolate, vit. B9 derivative)
transfers a variety of • methenyl = methine
one-carbon (C1) fragments, (-CH=)
the source of which is most often the
conversion of serine to glycine

• methylene (-CH2-)

irreversible reaction
catalyzed by methylen-THF-reductase
(MTHFR)
• methyl (-CH3)
 Thomas M. Devlin: Textbook of
Biochemistry with Clinical Correlations

Cofactor SAM
(S-adenosylmethionine)
it is the most common
cofactor of various methyl
transferases
Thomas M. Devlin: Textbook of Biochemistry with
Clinical Correlations
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
Metabolism of branched-
chain amino acids

Leucinosis (MSUD)
= maple syrup urine disease
BCKA-dehydrogenase
deficiency
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 Urea cycle
↓ Hs in the brain-inhibit neurontransmitter
.

Argininemia ↑ NHz & glutamine a orotic acid .

arginase deficiency
(see newborn screening)
Citrullinemia
argininosuccinate synthetase
deficiency
(see newborn screening)
https://www.newbornscreening.info/disorder_fact_sheet/

Ornithine transcarbamoylase
deficiency

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 Heme synthesis
Porhyrias
deficiencies of various
heme synthesis enzymes
(you don't have to learn the details)

All deficiencies lead to

reduced heme synthesis
and thus lack the feedback
inhibition of ALA-synthase
by heme

Accumulation of
5-aminolevulinic acid (ALA)
is manifested by
neurological symptoms,
accumulation of
porphyrinogens leads to
photosensitivity (oxidation
produces porphyrins that
accumulate in the skin)
Disorders of heme synthesis
and legends of vampires…

PORPHYRIAS
• inherited or acquired
• classification according to defective biosynthesis enzyme
• heme precursors accumulate in the body (skin) and are excreted in the urine
or faeces (dark color)
• neurological disorders, photosensitivity

lead poisoning – ALA accumulates (blood, urine)

(inhibition of porphobilinogen synthase)
 (just for interest ;)

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 Metabolism of
glycogen

Glycogenoses
(storage diseases)
deficiencies of various
enzymes of glycogen
metabolism
(you don't have to learn the details,
see the workbook)
Metabolism of galactose Galactosemia
deficiency of various enzymes of Gal degradation
see the workbook page 27
Metabolism of
fructose

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 Pentose cycle

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 Beta-oxidation of fatty acids (FA)

MCAD
medium chain acyl-CoA dehydrogenase deficiency
VLCAD
very long chain acyl-CoA dehydrogenase deficiency
LCHAD
long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
CPT I
carnitine-palmitoyltransferase I deficiency
CPT II
carnitine-palmitoyltransferase II deficiency
CAT
carnitine acyl-carnitine translocase deficiency

https://www.newbornscreening.info/disorder_fact_sheet/
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 cytosol
Transport of
fatty acids into
the mitochondria

CARNITINE
TRANSPORTER

fatty acid binding

carnitine
(Lys + Met) matrix of mitochondria

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

Cholesterol synthesis

cholesterol ketone bodies

 Smith-Lemli-Opitz syndrom
7-dehydrocholesterol reductase
deficiency

the last intermediate of cholesterol synthesis Cholesterol is essential for

the structure and function of
membranes, the synthesis of
steroid hormones,
acts as a regulatory molecule
in embryogenesis
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
7-dehydrocholesterol acts as a direct precursor of vitamin D synthesis in the skin,
the vitamin is then converted in the body to the hormone calcitriol
(regulation of calcium metabolism, effect on immunity, cell differentiation)
 Mitochondrial disorders are related to a disorder of ETC and ATP synthesis:
the NADH/NAD+ ratio increases, pyruvate and fatty acids accumulate
(due to reduced PDH and β-oxidation activity), resulting in
lactic acidosis and accumulation of TAG.
Lack of ATP leads to muscle weakness, cardiomyopathy, and CNS disorders.

Highly metabolically active organs are prone to damage – thay have high
energy requirements (brain, heart, skeletal muscle, liver, etc.)

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 Oxidative pathways in mitochondria
i.e. linked to the respiratory chain (ETC) via reduction cofactors (NAD, FAD)

• pyruvate dehydrogenase (PDH) oxidative decarboxylation of pyruvate

(from glucose and amino acids)
• -oxidation of fatty acids oxidation of fatty acids
• glutamate dehydrogenase (GMD) oxidative deamination of glutamate
• beginning of ketone body degradation oxidation of -OH-butyrate to
acetoacetate
• Krebs cycle oxidation of acetyl-CoA
(produced from all nutrients)
• respiratory chain (ETC) – transfers electrons to O2
(danger of radical formation)

regenerates NADH to NAD+

and reduced flavoenzymes (FADH2 to FAD)

and allows aerobic phosphorylation = production of most ATP in the cell

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations
 cerebroside

sulfatide

ganglioside

C18 unsaturated amino-alcohol Zdroj obrázků vpravo: Lipids. In: Koolman J, Röhm K,
ed. Color Atlas of Biochemistry. 3rd Edition.
Stuttgart: Thieme; 2012. doi:10.1055/b-005-148879
1) Phospholipids – most abundant membrane lipids
• Glycerophospholipids: „glycerol backbone“, only ester bonds:
glycerol-FA, glycerol-phosphate, phosphate-alcohol
• Sphingophospholipids: „sphingosine backbone“, FA is attached by an
amide bond to sphingosine = ceramide

2) Glycolipids – only in an outer membrane leaflet

• Sphingosine backbone only
• Ceramide + sugar(s) bound to the primary –OH of sphingosine
(do not contain phosphate)
a) Cerebrosides (ceramide + monosaccharide: galactose or glucose)
b) Sulfatides (= cerebroside containig sulfatated galactose)
c) Globosides (ceramide + more than one sugar: galactose, glucose,
N-acetylgalactose amine)
d) Gangliosides (= globoside + one or more acidic sugar moieties: NANA)
Source: Lipid Structure and Chemistry. In: Panini S, ed. Medical Biochemistry: An Essential Textbook.
2nd Edition. New York: Thieme; 2021. doi:10.1055/b000000285
Molecular Biology of THE CELL Sixth Edition / by Bruce Alberts and others / 2015
neutral sphingolipids acidic sphingolipids
 galactocerebroside

sulfatide
Ganglioside labeling ganglioside GM2
G = ganglioside
M = mono, D = di, T = tri, Q = quatro (four)
(indicates the number of molecules NANA)
numeric index = specifies the sequence of monomers
bound to ceramide

Gangliosides, i.e. glycolipids containing NANA, are

important from the point of view of storage diseases.
splits off NANA

splits off Gal

splits off GalNAc

(= hexosamine)

splits off NANA

splits off sulfate

released
molecule enzyme

Gal galactosidase
GalNAc hexosaminidase
NANA neuraminidase
Glc glucosidase
sulfát arylsulfatase
fosfocholin sphingomyelinase
(cleaves sphingomyelin)

• all reactions take place in the lysosomes

of phagocytic cells
• all enzymes are hydrolases
• most enzymes exist as isoenzymes
(e.g. hexosaminidase A and B)
• pH optimum: 3.5 – 5.5
• catalyze irreversible reactions
• are membrane bound in the lysosome
• they always split off one specific
molecule from the end of the chain
 for interest, only learn diseases that you know from genetics

Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations

 Degradation of GAG
mucopolysaccharidoses

• lysosomal enzyme deficiencies

• enzymes are named after the
molecule they split off
• uronic acids and amino sugars
are typical for GAGs
• aminosugars are often
sulfated
glycosaminoglycans (GAG)
= mucopolysaccharides
are polysaccharides
(part of proteoglycans) of the extracellular matrix
D-epimer

L-epimer

(formed by D-/L- epimerization from glucuronic acid)

released molecule enzyme

• N-acetylglucosamine N-acetylglucosaminidase
• sulfate sulfatase
• glucuronic acid glucuronidase glucuronic acid synthesis

• iduronic acid iduronidase

(occurs in heparan sulfate and dermatan sulfate)
-L-iduronidase deficiency

i.e. an enzyme that cleaves

iduronic acid from the end
of the glycosaminoglycan
chain
Thomas M. Devlin: Textbook of Biochemistry with Clinical Correlations