Download MBBS Biochemistry PPT 36 Biochemistry III Lecture Notes

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Catabolism of the Carbon Skeletons of amino acids and related

disorders:

? Catabolism of Phenylalanine and Tyrosine with genetic disorders

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? Arginine, Histidine, glutamate, glutamine and proline to -ketoglutarate

? Methionine, isoleucine, threonine and valine to Succinyl CoA

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? Degradation of branched chain aa (Leucine to Acetoacetate and Acetyl-CoA, Valine to -

Aminoisobutyrate and Succinyl-CoA and Isoleucine to Acetyl-CoA and Propionyl-CoA)

? Asparagine and Aspartate to Oxaloacetate

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Conversion of amino acids to Specialized products
Catabolism of Phenylalanine and Tyrosine with genetic disorders

Homogentisate Oxidase/

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Neonatal Tyrosinemia or

Or p-hydroxyphenylpyruvate hydroxylase

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Fig18.23: Lehninger Principles of Biochemistry by David L Nelson

Disorder related to phenylalanine catabolism

Phenylketonuria (PKU)

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? Genetic defect in phenylalanine hydroxylase, first enzyme in

catabolic pathway for phenylalanine, is responsible for disease

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phenylketonuria (PKU),most common cause of elevated levels of

phenylalanine (hyperphenylalaninemia)

? Excess phenylalanine is transaminated to Phenylpyruvate

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? The "spillover" of Phenylpyruvate (a phenylketone) into urine

? High concentration of phenylalanine itself gives rise to brain

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dysfunction.
Cont--

? Phenylalanine

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hydroxylase

requires

the

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cofactor

tetrahydrobiopterin, which carries electrons from NADH to O2

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and becomes oxidized to dihydrobiopterin

? It is subsequently reduced by enzyme dihydrobiopterin

reductase in a reaction that requires NADH

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? Diet low in phenylalanine can prevent the mental retardation of

PKU

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Disorder related to Tyrosine catabolism

Alkaptonuria

? Metabolic defect in alkaptonuria is a defective homogentisate oxidase the

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enzyme that catalyzes homogentisate to Maleylacetoacetate

? Large amounts of homogentisate are excreted and urine darkens on

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exposure to air due to oxidation of excreted homogentisate

? This autooxidizes to the corresponding quinone, which polymerizes to form

an intensely dark color

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? Late in the disease, there is arthritis and connective tissue pigmentation

(ochronosis) due to oxidation of homogentisate to benzoquinone acetate,

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which polymerizes and binds to connective tissue
Type I Tyrosinemia

? Several metabolic disorders are associated with the tyrosine

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catabolic pathway

? Probable metabolic defect in type I tyrosinemia (tyrosinosis) is

at fumarylacetoacetate hydrolase

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? Untreated acute and chronic tyrosinosis leads to death from

liver failure, renal tubular dysfunction, rickets and

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polyneuropathy

Type II Tyrosinemia

? Alternate metabolites of tyrosine are also excreted in type II

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tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine

aminotransferase produces accumulation and excretion of

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tyrosine and metabolites

? Leads to eye and skin lesions and mental retardation
Type III Tyrosinemia

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? Neonatal Tyrosinemia or type III tyrosinemia, due to lowered

activity

of

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p-hydroxyphenylpyruvate

dioxygenase/

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p-

hydroxyphenylpyruvate hydroxylase

? It can cause learning problems, seizures, and loss of balance

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? Therapy employs a diet low in protein, tyrosine and

phenylalanine

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Catabolic pathways of five aa to -ketoglutarate

Proline dehydrogenase/

1-pyrroline-5-carboxylate dehydrogenase/

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Fig18.26: Lehninger Principles of Biochemistry by David L Nelson
Disorder related to Proline catabolism

Type I hyperprolinemia

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? The metabolic block in type I hyperprolinemia is at proline

dehydrogenase/proline oxidase

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? Some individuals with hyperprolinemia type I exhibit seizures,

intellectual disability, or other neurological or psychiatric

problems

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Type II hyperprolinemia

? The metabolic block in type II hyperprolinemia is at 1-

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pyrroline-5-carboxylate dehydrogenase, which also participates

in the catabolism of arginine, ornithine, and hydroxyproline

? It leads to seizures or intellectual disability.

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Catabolic pathways of four aa to Succinyl-CoA

Cystathione

Fig18.27: Lehninger Principles of Biochemistry by David L Nelson

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Cont--

? Catabolism of isoleucine, methionine, and valine to propionyl-

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CoA

? Propionyl-CoA, product of odd-chain fatty acid degradation, is

converted, to succinyl-CoA by a series of reactions involving the

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participation of biotin and coenzyme B12
Degradation and Resynthesis of Methionine

Biosynthesis of S-adenosylmethionine

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from methionine and ATP is catalyzed

by methionine adenosyltransferase

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(MAT)

Fig 20.8. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed

Disorder related to Methionine degradation

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Hyper Homocysteinemia

? Elevations in plasma homocysteine (Hcy) as a result of rare

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deficiencies in cystathionine -synthase of the transsulfuration

pathway causes homocysteine to accumulate and remethylation

leads to high levels of methionine in patients

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? Elevated homocysteine and decreased folic acid levels in

pregnant women are associated with increased incidence of

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neural tube defects (improper closure, as in spina bifida) in fetus
Cont--
? The lens of eye is frequently dislocated after the age of 3, and other

ocular abnormalities occur

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? Mental retardation is frequently the first indication of this deficiency

? Attempts at treatment include restriction of methionine intake and

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feeding of betaine (or its precursor, choline)

? In some cases significant improvement by feeding pyridoxine (vit B6)

? Supplementation with folate reduces the risk of such defects

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Degradation of Branched chain amino acids
? Mitochondrial branched-chain -keto acid dehydrogenase

complex consists of five components:

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E1: thiamin pyrophosphate (TPP)-dependent branched chain -

ketoacid decarboxylase
E2: dihydrolipoyl transacylase (contains lipoamide)

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E3: dihydrolipoamide dehydrogenase (contains FAD)
Protein kinase
Protein phosphatase

Catabolism of Leucine to Acetoacetate and Acetyl-CoA

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Methylcrotonyl CoA carboxylase

-keto acid decarboxylase complex

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Methylglutaconyl-CoA hydralase

Isovaleryl CoA dehydrogenase

HMG CoA lyase

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Fig 29.20 and 29.21. Harper's Illustrated Biochemistry 30th Edition
Catabolism of Valine to -Aminoisobutyrate and Succinyl-CoA

Enoyl CoA hydratase

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-hydroxyisobutyryl CoA hydrolase

-keto acid decarboxylase complex

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Methacrylyl CoA dehydrogenase

Fig 29.20 and 29.23. Harper's Illustrated Biochemistry 30th Edition

Catabolism of Isoleucine to Acetyl-CoA and Propionyl-CoA

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Amino acid transaminase

-hydroxybutyryl CoA dehydrogenase

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-keto acid decarboxylase complex

Fig 29.20 and 29.22. Harper's Illustrated Biochemistry 30th Edition
Disorder related to Branch chain aa degradation

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? Biochemical defect in maple syrup urine disease (MSUD)

involves -keto acid decarboxylase complex (thiamine

pyrophosphate, FAD, NAD, lipoate and CoA)

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? Plasma and urinary levels of leucine, isoleucine, valine, and

their -keto acids and -hydroxy acids (reduced -keto acids)

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are elevated and accumulated in blood and spil over into the

urine

? This condition is called MSUD or branched-chain ketonuria

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suggests maple syrup, or burnt sugar.

? Signs and symptoms of MSUD include fatal ketoacidosis,

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neurological derangements, mental retardation, and a maple

syrup odor of urine

? Early diagnosis by enzymatic analysis is essential to avoid brain

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damage and early mortality by replacing dietary protein by an

aa mixture that lacks leucine, isoleucine, and valine
Catabolism of Asparagine and Aspartate to Oxaloacetate

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Fig18.29: Lehninger Principles of Biochemistry by David L Nelson

Cont--

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? L-asparaginase is an effective chemotherapeutic agent in the

treatment of cancers that must obtain asparagine from the

blood, particularly acute lymphoblastic leukemia.

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Conversion of amino acids to Specialized

products

Introduction

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? In addition to serving as building blocks for proteins, amino

acids are precursors of many nitrogen-containing compounds

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that have important physiologic functions

? These molecules include porphyrins (involved in heme

biosynthesis),

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hormones,

purines,

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and

pyrimidines,

neurotransmitters.

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Conversion of arginine, ornithine and proline to specialized products

Fig 30.1. Harper's Illustrated Biochemistry 30th Edition

Creatine & Creatinine

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? Creatinine is formed in muscle

from creatine phosphate by

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irreversible,

non-enzymatic

dehydration,

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and

loss

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of

phosphate

? Glycine, arginine, and methionine

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all

participate

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in

creatine

biosynthesis

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Fig 30.13. Harper's Illustrated Biochemistry 30th Edition
Cont--

? Creatine converted into creatine phosphate by creatine kinase

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using ATP as a phosphate donor

? Presence of creatine kinase in the plasma is indicative of heart

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damage and is used in the diagnosis of myocardial infarction

Conversion of cysteine to Taurine

? Three

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enzyme

catalyzed

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reactions convert cysteine to

taurine

? Taurine displace the coenzyme

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A moiety of cholyl-CoA to form

the bile acid taurocholic acid

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Fig 30.4. Harper's Illustrated Biochemistry 30th Edition
Biosynthesis of hippurate from glycine

? Many metabolites and pharmaceuticals are

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excreted as water soluble glycine conjugates

? Ex. include glycocholic acid and hippuric acid

formed from the food additive benzoate

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? Many drugs, drug metabolites, and other

compounds with carboxyl groups are

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conjugated with glycine, which makes them

more water-soluble and thereby facilitates

their excretion in urine

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Fig 30.5. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Histidine

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? Decarboxylation of histidine to

histamine is catalyzed by the pyridoxal

5-phosphate-dependent

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enzyme

histidine decarboxylase

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? Histamine functions in allergic

reactions and gastric secretion

Fig 30.6. Harper's Illustrated Biochemistry 30th Edition

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Derivatives of Methionine

Methionine adenosyl transferase

? These polyamines function in

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cell proliferation and growth,

are growth factors for cultured

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mammalian

cells, and

stabilize

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intact

cells,

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subcellular organelles, and

membranes

? They bear multiple positive

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charges, polyamines readily

associate with DNA and RNA

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Fig 30.9. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Tryptophan

? Hydroxylation of tryptophan to 5-hydroxytryptophan by liver

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tryptophan hydroxylase subsequent decarboxylation forms

serotonin a potent vasoconstrictor and stimulator of smooth

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muscle contraction.

? Catabolism of serotonin is initiated by deamination to 5-

hydroxyindole-3-acetate, a reaction catalyzed by monoamine

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oxidase
Cont--

? N-Acetylation of serotonin, followed by its O-methylation in the

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pineal body, forms melatonin

? Kidney tissue, liver tissue, and fecal bacteria all convert

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tryptophan to tryptamine, then to indole 3-acetate

? The principal normal urinary catabolites of tryptophan are 5-

hydroxyindoleacetate and indole 3-acetate.

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Fig 30.11. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Tyrosine

? Neural cells convert tyrosine to epinephrine and norepinephrine

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? Dopa is also an intermediate in the formation of melanin,

different enzymes hydroxylate tyrosine in melanocytes

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? Dopa decarboxylase, a PLP-dependent enzyme, forms

dopamine.

Cont--

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? Subsequent hydroxylation, catalyzed by dopamine -oxidase

forms norepinephrine

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? In

adrenal

medulla,

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phenylethanolamine-N-

methyltransferaseutilizes S-adenosylmethionine to methylate

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the primary amine of norepinephrine, forming epinephrine

? Tyrosine is also a precursor of triiodothyronine and thyroxine
Derivatives of Tyrosine: Epinephrine

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Fig 30.12. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Tyrosine: Melanin

DM Vasudevan' s Textbook of Biochemistry for Medical Students-6th Ed

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Derivatives of Tyrosine: T3 and T4

DM Vasudevan' s Textbook of Biochemistry for Medical Students-6th Ed

Disorder related to Tyrosine derivative

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Albinism

? A deficiency of tyrosinase in melanocytes causes one form of albinism; it is

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inherited as an autosomal recessive disorder

? Pigmentation of the skin, hair and iris is reduced and the eyes may appear

pink

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? Reduced pigmentation of the iris causes photosensitivity, and decreased

skin pigmentation is associated with an increased incidence of certain skin

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cancers

? The tyrosinase involved in catecholamine synthesis is a different

isoenzyme, controlled by a different gene; consequently, adrenaline

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(epinephrine) metabolism is normal
Metabolism of -AminoButyrate (GABA)

Active form of Vit B6

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Fig 30.14. Harper's Illustrated Biochemistry 30th Edition

Disorder related to GABA

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4-hydroxybutyric aciduria
? Defects in succinic semialdehyde dehydrogenase, are

responsible for 4-hydroxybutyric aciduria a rare metabolic

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disorder of -aminobutyrate catabolism

? Characterized by the presence of 4-hydroxybutyrate in urine,

plasma and cerebrospinal fluid

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? No present treatment is available for the accompanying mild to

severe neurologic symptoms.
Group Discussion

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? Subtopics of previous and today's class discussed in groups.
? Next integrated class on Protein metabolism by me and from

department of Pediatrics (discussed inborn error of metabolism

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case studies).

Thank you