Download MBBS Biochemistry PPT 36 Biochemistry III Lecture Notes

Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 36 Biochemistry III Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.


Department of Biochemistry

Learning Objectives

Catabolism of the Carbon Skeletons of amino acids and related

disorders:

? Catabolism of Phenylalanine and Tyrosine with genetic disorders

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

? Methionine, isoleucine, threonine and valine to Succinyl CoA

? 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

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

Homogentisate Oxidase/

Neonatal Tyrosinemia or

Or p-hydroxyphenylpyruvate hydroxylase

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

Disorder related to phenylalanine catabolism

Phenylketonuria (PKU)

? Genetic defect in phenylalanine hydroxylase, first enzyme in

catabolic pathway for phenylalanine, is responsible for disease

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

phenylalanine (hyperphenylalaninemia)

? Excess phenylalanine is transaminated to Phenylpyruvate

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

? High concentration of phenylalanine itself gives rise to brain

dysfunction.
Cont--

? Phenylalanine

hydroxylase

requires

the

cofactor

tetrahydrobiopterin, which carries electrons from NADH to O2

and becomes oxidized to dihydrobiopterin

? It is subsequently reduced by enzyme dihydrobiopterin

reductase in a reaction that requires NADH

? Diet low in phenylalanine can prevent the mental retardation of

PKU

Disorder related to Tyrosine catabolism

Alkaptonuria

? Metabolic defect in alkaptonuria is a defective homogentisate oxidase the

enzyme that catalyzes homogentisate to Maleylacetoacetate

? Large amounts of homogentisate are excreted and urine darkens on

exposure to air due to oxidation of excreted homogentisate

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

an intensely dark color

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

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

which polymerizes and binds to connective tissue
Type I Tyrosinemia

? Several metabolic disorders are associated with the tyrosine

catabolic pathway

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

at fumarylacetoacetate hydrolase

? Untreated acute and chronic tyrosinosis leads to death from

liver failure, renal tubular dysfunction, rickets and

polyneuropathy

Type II Tyrosinemia

? Alternate metabolites of tyrosine are also excreted in type II

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

aminotransferase produces accumulation and excretion of

tyrosine and metabolites

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

? Neonatal Tyrosinemia or type III tyrosinemia, due to lowered

activity

of

p-hydroxyphenylpyruvate

dioxygenase/

p-

hydroxyphenylpyruvate hydroxylase

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

? Therapy employs a diet low in protein, tyrosine and

phenylalanine

Catabolic pathways of five aa to -ketoglutarate

Proline dehydrogenase/

1-pyrroline-5-carboxylate dehydrogenase/

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

Type I hyperprolinemia

? The metabolic block in type I hyperprolinemia is at proline

dehydrogenase/proline oxidase

? Some individuals with hyperprolinemia type I exhibit seizures,

intellectual disability, or other neurological or psychiatric

problems

Type II hyperprolinemia

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

pyrroline-5-carboxylate dehydrogenase, which also participates

in the catabolism of arginine, ornithine, and hydroxyproline

? It leads to seizures or intellectual disability.
Catabolic pathways of four aa to Succinyl-CoA

Cystathione

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

Cont--

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

CoA

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

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

participation of biotin and coenzyme B12
Degradation and Resynthesis of Methionine

Biosynthesis of S-adenosylmethionine

from methionine and ATP is catalyzed

by methionine adenosyltransferase

(MAT)

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

Disorder related to Methionine degradation

Hyper Homocysteinemia

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

deficiencies in cystathionine -synthase of the transsulfuration

pathway causes homocysteine to accumulate and remethylation

leads to high levels of methionine in patients

? Elevated homocysteine and decreased folic acid levels in

pregnant women are associated with increased incidence of

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

? Mental retardation is frequently the first indication of this deficiency

? Attempts at treatment include restriction of methionine intake and

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

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

complex consists of five components:

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

ketoacid decarboxylase
E2: dihydrolipoyl transacylase (contains lipoamide)
E3: dihydrolipoamide dehydrogenase (contains FAD)
Protein kinase
Protein phosphatase

Catabolism of Leucine to Acetoacetate and Acetyl-CoA

Methylcrotonyl CoA carboxylase

-keto acid decarboxylase complex

Methylglutaconyl-CoA hydralase

Isovaleryl CoA dehydrogenase

HMG CoA lyase

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

Enoyl CoA hydratase

-hydroxyisobutyryl CoA hydrolase

-keto acid decarboxylase complex

Methacrylyl CoA dehydrogenase

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

Catabolism of Isoleucine to Acetyl-CoA and Propionyl-CoA

Amino acid transaminase

-hydroxybutyryl CoA dehydrogenase

-keto acid decarboxylase complex

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

? Biochemical defect in maple syrup urine disease (MSUD)

involves -keto acid decarboxylase complex (thiamine

pyrophosphate, FAD, NAD, lipoate and CoA)

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

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

are elevated and accumulated in blood and spil over into the

urine

? This condition is called MSUD or branched-chain ketonuria

suggests maple syrup, or burnt sugar.

? Signs and symptoms of MSUD include fatal ketoacidosis,

neurological derangements, mental retardation, and a maple

syrup odor of urine

? Early diagnosis by enzymatic analysis is essential to avoid brain

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

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

Cont--

? L-asparaginase is an effective chemotherapeutic agent in the

treatment of cancers that must obtain asparagine from the

blood, particularly acute lymphoblastic leukemia.
Conversion of amino acids to Specialized

products

Introduction

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

acids are precursors of many nitrogen-containing compounds

that have important physiologic functions

? These molecules include porphyrins (involved in heme

biosynthesis),

hormones,

purines,

and

pyrimidines,

neurotransmitters.
Conversion of arginine, ornithine and proline to specialized products

Fig 30.1. Harper's Illustrated Biochemistry 30th Edition

Creatine & Creatinine

? Creatinine is formed in muscle

from creatine phosphate by

irreversible,

non-enzymatic

dehydration,

and

loss

of

phosphate

? Glycine, arginine, and methionine

all

participate

in

creatine

biosynthesis

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

? Creatine converted into creatine phosphate by creatine kinase

using ATP as a phosphate donor

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

damage and is used in the diagnosis of myocardial infarction

Conversion of cysteine to Taurine

? Three

enzyme

catalyzed

reactions convert cysteine to

taurine

? Taurine displace the coenzyme

A moiety of cholyl-CoA to form

the bile acid taurocholic acid

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

? Many metabolites and pharmaceuticals are

excreted as water soluble glycine conjugates

? Ex. include glycocholic acid and hippuric acid

formed from the food additive benzoate

? Many drugs, drug metabolites, and other

compounds with carboxyl groups are

conjugated with glycine, which makes them

more water-soluble and thereby facilitates

their excretion in urine

Fig 30.5. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Histidine

? Decarboxylation of histidine to

histamine is catalyzed by the pyridoxal

5-phosphate-dependent

enzyme

histidine decarboxylase

? Histamine functions in allergic

reactions and gastric secretion

Fig 30.6. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Methionine

Methionine adenosyl transferase

? These polyamines function in

cell proliferation and growth,

are growth factors for cultured

mammalian

cells, and

stabilize

intact

cells,

subcellular organelles, and

membranes

? They bear multiple positive

charges, polyamines readily

associate with DNA and RNA

Fig 30.9. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Tryptophan

? Hydroxylation of tryptophan to 5-hydroxytryptophan by liver

tryptophan hydroxylase subsequent decarboxylation forms

serotonin a potent vasoconstrictor and stimulator of smooth

muscle contraction.

? Catabolism of serotonin is initiated by deamination to 5-

hydroxyindole-3-acetate, a reaction catalyzed by monoamine

oxidase
Cont--

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

pineal body, forms melatonin

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

tryptophan to tryptamine, then to indole 3-acetate

? The principal normal urinary catabolites of tryptophan are 5-

hydroxyindoleacetate and indole 3-acetate.

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

? Neural cells convert tyrosine to epinephrine and norepinephrine

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

different enzymes hydroxylate tyrosine in melanocytes

? Dopa decarboxylase, a PLP-dependent enzyme, forms

dopamine.

Cont--

? Subsequent hydroxylation, catalyzed by dopamine -oxidase

forms norepinephrine

? In

adrenal

medulla,

phenylethanolamine-N-

methyltransferaseutilizes S-adenosylmethionine to methylate

the primary amine of norepinephrine, forming epinephrine

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

Fig 30.12. Harper's Illustrated Biochemistry 30th Edition

Derivatives of Tyrosine: Melanin

DM Vasudevan' s Textbook of Biochemistry for Medical Students-6th Ed
Derivatives of Tyrosine: T3 and T4

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

Disorder related to Tyrosine derivative

Albinism

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

inherited as an autosomal recessive disorder

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

pink

? Reduced pigmentation of the iris causes photosensitivity, and decreased

skin pigmentation is associated with an increased incidence of certain skin

cancers

? The tyrosinase involved in catecholamine synthesis is a different

isoenzyme, controlled by a different gene; consequently, adrenaline

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

Active form of Vit B6

Fig 30.14. Harper's Illustrated Biochemistry 30th Edition

Disorder related to GABA

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

responsible for 4-hydroxybutyric aciduria a rare metabolic

disorder of -aminobutyrate catabolism

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

plasma and cerebrospinal fluid

? No present treatment is available for the accompanying mild to

severe neurologic symptoms.
Group Discussion

? 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

case studies).

Thank you

This post was last modified on 05 April 2022