Renal Block Biochemistry of Phenylketonuria PKU Maple Syrup Urine Disease MSUD Albinism Homocyteinuria Alkaptonuria 1 Lecture Dr Ahmed H Mujamammi Inborn Errors of aa Metabolism ID: 347337
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Inborn Errors of Amino Acid Metabolism(Renal Block)
Biochemistry of:
Phenylketonuria (PKU)Maple Syrup Urine Disease (MSUD)AlbinismHomocyteinuriaAlkaptonuria
1 Lecture Dr.
Ahmed H.
MujamammiSlide2
Inborn Errors of aa MetabolismCaused by enzyme loss or deficiency due to gene loss or gene mutationSlide3
Phenylketonuria (PKU)Due to deficiency of
phenylalanine hydroxylase enzymeMost common disease of aa metabolismResults in hyperphenylalaninemiaSlide4
Phenylketonuria (PKU)Classic PKU:
Due to deficiency of phenylalanine hydroxylaseConversion of Phe to Tyr requires tetrahydrobiopterin (BH4)Even if phenylalanine hydroxylase level is normalThe enzyme will not function without BH4
Hence Phe is accumulatedSlide5
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.The pathway of phenylalanine degradation
Page 1009
Phenylalanine hydroxylase
Phenylalanine
accumulatedSlide6
Phenylketonuria (PKU)Atypical hyperphenylalaninemia:
Due to deficiency of BH4Caused by the deficiency of:Dihydropteridine reductaseDihydrobiopterin synthetaseCarbinolamine dehydrataseSlide7
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Formation, utilization, and regeneration of 5,6,7,8-tetrahydrobiopterin (BH4) in the phenylalanine hydroxylase reaction
Page 1010
GTP
Dihydrobiopterin
synthetaseSlide8
Characteristics of PKUIn the absence of BH
4, Phe will not be converted to TyrSlide9
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.
Page 1010
BH
2
Phe accumulatedSlide10
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Melanin biosynthesis from tyrosine
Page 1002
No or less
tyrosine
Melanin
No or less melanin
Light skin in PKU patientsSlide11
Characteristics of PKUTyr will not be converted to catecholamine neurotransmitters
Synthesis of catecholamines requires BH4Slide12Slide13
Characteristics of PKUTrp will not be converted to serotonin (a neurotransmitter) as it requires BH
4Slide14
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Synthesis of serotonin
Page 1025Slide15
Characteristics of PKUCNS symptoms: Mental retardation, failure to walk or talk, seizures, etc.
HypopigmentationDeficiency of melaninHydroxylation of tyrosine by tyrosinase is inhibited by high phe conc.Slide16
Characteristics of PKUElevated phenylalanine in tissues, plasma, urine
Phe is degraded to phenyllactate, phenylacetate, and phenylpyruvateGives urine a mousy odorSlide17
Cause of mousy urine smell in PKUSlide18
Characteristics of PKUPrenatal diagnosis is done by detecting gene mutation in fetus
Neonatal diagnosis in infants is done by measuring blood phe levelsTreatment:Life long phe-restricted dietSlide19
Maple Syrup Urine DiseaseDue to deficiency of
branched chain a-ketoacid dehydrogenaseThe enzyme
decarboxylates leucine, isoleucine and valineThese aa accumulate in bloodSymptoms: mental retardation, physical disability, metabolic acidosis, etc.Maple syrup odor of urineSlide20
Maple Syrup Urine DiseaseTypes:
Classic type: Most common, due to little or no activity of a-ketoacid dehydrogenaseIntermediate and intermittent forms: Some enzyme activity, symptoms are milder
Thiamin-responsive form: High doses of thiamin increases a-ketoacid dehydrogenase activitySlide21
Degradation of branched-chain amino acids: valine, isoleucine and leucine.
Deficiency of branched chain a-keto acid dehydrogenase leads to MSUD.
Valine, Isoleucine,
Leucine and their
keto acids
accumulatedSlide22
Maple Syrup Urine DiseaseTreatment:
Limited intake of leucine, isoleucine and valineSlide23
AlbinismA disease of tyrosine metabolism
Tyrosine is involved in melanin productionMelanin is a pigment of hair, skin, eyesDue to tyrosinase deficiencyMelanin is absent in albino patientsHair and skin appear white
Vision defects, photophobiaSlide24
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Melanin biosynthesis from tyrosine: Deficiency of tyrosinaseleads to albinisim
Page 1002
Tyrosinase
MelaninSlide25
HomocystinuriaDue to defects in
homocysteine metabolismDeficiency of cystathionine b-synthase
Converts homocysteine to cystathioneHigh plasma and urine levels of homocysteineHigh plasma homocysteine is a risk factor for atherosclerosis and heart disease
Skeletal abnormalities, osteoporosis, mental retardation, displacement of eye lensSlide26
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Methionine degradation pathway: Deficiency of cystathione b-synthase leads to homocystinuria / homocysteinemia
Page 1002
Cystathione b-synthase
Methionine and its
metabolites are
accumulated
Cysteine becomes
deficientSlide27
Homocystinuria
Treatment:Oral administration of vitamins B6, B12 and folateVitamin B
6 is a cofactor for cystathionine b-synthaseMethionine-restricted dietSlide28
Homocysteinemia
Hyperhomocysteinemia is also associated with:Neural tube defect (spina bifida)Vascular disease (atherosclerosis)Heart diseaseSlide29
Voet Biochemistry 3e© 2004 John Wiley & Sons, Inc.Methionine degradation pathway: Deficiency of cystathione b-synthase leads to hyperhomocystinuria / hyperhomocysteinemia
Page 1002
Cystathione b-synthase
Hyperhomocysteinemia
Deficiency of:
Tetrahydrofolate
Methionine synthase
Vitamin B
6
, B
12
Folic acid
Neural
tube
defect
+Slide30
AlkaptonuriaA rare disease of tyrosine degradation
Due to deficiency of homogentisic acid oxidaseHomogentisic acid is accumulated in tissue and cartilageHomogentisic aciduria: elevated homogentisic acid in urineSlide31
AlkaptonuriaHomogentisic
acid is oxidized to dark pigment in urine over timeArthritis, black pigmentation of cartilage and tissueUsually asymptomatic until adulthoodRestricted intake of tyrosine and phenylalanine reduces homogentisic acid and dark pigmentationSlide32
Degradation of tyrosine
Deficiency of homogentisic acid oxidase leads to alkaptonuria
Homogentisate oxidase