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Inborn Errors of Amino Acid Metabolism Inborn Errors of Amino Acid Metabolism

Inborn Errors of Amino Acid Metabolism - PowerPoint Presentation

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Inborn Errors of Amino Acid Metabolism - PPT Presentation

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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Slide1

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 BH4Slide12
Slide13

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