Sulphur Containing Amino Acids
They are methionine,cyseine,cystine.Methioinine is essential.
It serves as precursors for the synthesis of cysteine and cystine.
Both are non essential.
Cysteine and cystine are interconvertable.
The sulphur-containing AA are an exclusive dietary source of sulphur in the body
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Sulphur containing Amino Acids
Cystine Cysteine Methionine
CH3
S
(CH2)3CHNH2
COOHMethionine
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Methionine is essential ,it serves as precursor for the synthesis of cysteine and cystine.
Methionine and cysteine present in proteins.
The sulfur containing amino acids are almost an exclusive dietary source of sulfur to the body.• A
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Methionine (Amino Acid that form Succinyl CoA)
It is one of four amino acids that form succinyl CoA.
It is converted to s-adenosylmethionine(SAM),the major methyl- group donor in one carbon metabolism.
It is also a source of homocysteine – a metabolite associated with atherosclerosis and vascular disease.
Metabolism of Methionine
3 partsUtilization of methionine for transmethylation reactions.
Conversion of methionine to cysteine and cystine.
Degradation of cysteine and its conversion to specialized products
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Metabolism of Sulphur containing Amino Acids(Cystein, cystine Methionine:
Cysteine Biosynthesis
Cysteine is synthesized from essential A.A.
methionine
Ist Step:
ATP+Methionine S-Adenosyl methionine
SAM serve as precursor for methyl group
ex. Nor epinephrine EpinephrineMethionine adenosyl transferease
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S-Adenosylmethionine is highly reactive due to the presence of a positive charge. The enzyme involved in the transfer of methyl group are called methyltransferase.
S-AM transfer the methyl group to an acceptor and gets itself converted to S- adenosylhomocysteine.
The loss of free energy in this reaction makes the methyl transfer irreversable.
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2nd step:
S-Adenosylmethionine S-Adenosyl homocysteine
SAM release its methyl group to a methyl acceptor forming S- Adenosyl homocysteine
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3rd Step:
S-Adenosyl homocysteine Homocysteine+ Adenosine
S-Adenosyl homocysteine is cleaved by the homocysteinase enzyme to give homocysteine and adenosine need H2O and doesn't need any catalytic action.
S-Adenosyl homocystinase
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S-Adenosylhomocysteine is hydrolysed to homocysteine and adenosin
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4th Step:
Homocysteine + Serine Cystathionine
This step is a condensation of homocystine with AA serine to form cystathionine need catalytic enzyme synthetaseCystathionine synthetase
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5th step:
Cystathionine
Cystasthionine lyase
Cysteine+ α ketobutyrateLyses of cysthionine to form cysteine and αketobutyrate by the enzyme cystathionine lyase.
Fate: Cysteine is needed for protein synthesis and other body need.
αketobutyrate is decarboxylated to propionyl CoA.
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• Degradation &resynthesis of methionine
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After donation of the methyl group ,S- Adenososylhomocysteine is hydrolysed to homocystein and Adenosine.
Homocysteine has 2 fate:
Fate of homocysteine
If there is a deficiency of methionine ,homocysteine may be remethylated to methionine.Or if there is adequate amount of methionine ie stores are adequate homocysteine may enter the transsulfuration pathway ,where it is converted to cysteine
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Fate1: if inadequate stores of methionine
Homocysteine accept a methyl group from N –methyl THF in a reaction requiring methylcobolamine (co B12) .
The methyl group is transferred from B12 derivative to homocysteine
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• Degradation &resynthesis of methionine
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Metabolic Diseases Related to Sulphur Amino Acids
Homocysteinuria:
# It is related to methionine metabolism.
# It is autosomal recessive disease.
#It is inborn error of metabolism due to deficiency of Cystathionine synthetase. .(step 4).
#Accumulation of homocystine and Its appearance in the urine.
# Cataract, Mental retardation, Taller than other group.
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#Harmful treatable disease if diagnosed early.
#Diagnosis by amino acids analysis in the urine.
#Increase homocystine in the urine.#Treatment is supply of milk with no methionine and added cystein.
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Relationship of homocysteine to vascular disease
Elevation of homocysteine accelerate oxidative damage inflammation and endothelial dysfunction ,and independent risk factor for occulsive vascular disease.
Epidemiological studies have shown that that plasma homocysteine is inversly related to the plasma levels of folate, B12 and B6 ,the three vitamine that involved in the conversion of homocysteine to methionine and cysteine
Supplementation of these vitamines has been shown to reduce circulating levels of homocysteine .
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Relationship of homocysteine to vascular disease
In addition large elevation of homocysteine in blood as a result of rare deficiency in cystathionine synthetase are seen in patients with classic homocysteinuria .
These individuals experience premature vascular disease with about 25% dying from thrombotic complications before 30 years of age.
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Cystinuria
#Autosomal recessive inherited abnormality of tubular reabsorption.
#Excessive excretion of dibasic amino acids cystine, ornithine,arginine &lysine (25-40)times normal.
#The defect is in the renal reabsorption mechanism
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Cystinuria
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#Cystine is relatively insoluble and become of a high concentration in the urine.
#precipitate to form renal calculi. (cystine calculi).
#Diagnosis by demonstrating excessive excretion of cystine in the urine.
#Management is to prevent calculi formation by reducing urine concentration. High fluid intake, urinary alkalinizer , penicillamine.
Cystinosis
#Rare but serious disorders of cystine metabolism.
#Excessive deposition of cystine in different organ, kidney, bone marrow, cornea, conjunctiva.
#Generalized aminoaciduria with glucosuria.
#Harmful untreatable disease end with early death.
#Defect is unknown, may be due to impaired in the transport of cystine from the affected cells.
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Creatinine
# It is one of the final product of Arginine, Glycine & Methionine.
#Creatine present in muscles, brain& blood.
#Creatinine is the anhydride of creatine formed by irreversible non enzymatic dehydration of muscle creatine.• A
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Arginine
Arginine-glycine transamidination
GlycocyamineATP
ADP
5-Adenosylmethionine
5-Adenosylhomocystine
Kidney
Creatine phosphate
Muscle- non enzymatic dehaydration
H2O+piCreatinine
Schematic presentation of creatinine biosynthesis
NH2
C
NH4
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Creatinine is normally released from skeletal muscles to the circulation in a constant manner and excreted through complete filtration without reabsorption.
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Interpretation of serum creatinine should consider certain factors:
1. Lower in children than adult, lower in female than male & lower during pregnancy .
2.Certain drugs(salicylate&cimitidine) increase creatinine by inhibiting tubular secretion of creatinine.
3.Some endogenous substances (acetoacetate) may affect the analytical method of measurement of creatinine
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Serum Creatinine is indirect measurement of Glomerular Filtration Rate (GFR)
Increase in serum creatinine is likely due to a fall in GFR.
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Increase serum Creatinine( Decrease GFR) could be due to:
1.Any diseases lead to impairment of renal perfusion.
2.Diseases lead to loss of the functioning nephrons (Acute&chronic glomerulonephritis).
3.Diseases whose pressure is increased on tubular side of the nephrons.
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Serum Creatinine is indirect measurement of Glomerular Filtration Rate (GFR)
Increase in serum creatinine is likely due to a fall in GFR.
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Creatinine can be used for in the measurement of creatinine clearance (index of GFR)
UV
----------------
PX1440U: Urine Creatinine.
V: 24 hours urine volume.
P: Plasma creatinine.
I440: 24X60
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Normal Range: Serum Creatinine(0.6-1.4)mg/dl.
Creatinine Clearance:(80-120)ml/min.
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* Branched chain AA
Valine
Leucine
Isoleucine
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Valine,leucine and isoleucine are branched chain essential amino acids.
These three AA initially undergo a common pathway and then diverge to result in different end product.
Based on their product they are either glycogenic or ketogenic
Valine-------------glycogenic
Leucine------------ketogenic
Isoleucine-----------both glycogenic&ketogenic
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The first three metabolic reactions are common to the branched chain amino acids
1. Transamination.
2. Oxidative decarboxylation.
3. Dehydrogenation.
Transamination: the 3AA undergo transamination to form their respective ketoacids.
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• Schematic presentation of metabolic pathways of Br. Chain Amino Acids
End result
Valine--------propionyl CoA--------GlucoseLeucine-------Acetyl CoA+Acetoacetate
Isoleucine------- Propionyl CoA + Acetyl CoA
Valine--------Glycogenic
Leucine------- Ketogenic
Isoleucine------Both
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Metabolic Disorders of Branched Chain A.A.
Maple Syrup Urine Disease
Autosomal recessive disease.
Block in the metabolism of leucine, Isoleucine.
The oxidative decarboxylation of αketoacids do not occur.
Branched chain ketoacids accumulate in the urine.
Occurs at the end of the Ist week of life.
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Intolerance to milk.
Mental retardation.
Smell of the urine is just like burned sugarDiagnosis by urine chromatography.
Harmful untreatable disease.Extensive brain damage in those who survive.
Death occurs at the end of Ist year.• A
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Histidine:
Usually metabolized through histidase which act on histidine to split off ammonia and form urocanate.
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Histidine on decarboxylation ,gives the histamine which regulate HCl secretion by gastric mucosa
Histidinemia: due to defect histidase.
High level of histidine.
Mentally retarded with defect in speech
Harmful untratable
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Arginine:
Arginine is cleaved by arginase to give urea and produce ornithine
Hyperargininemia is inborn error of metabolism of arginine due to the defect in the enzyme arginase.
Nitric oxide(NO): arginine is the substrate for the production of nitric oxide(NO)by the enzyme nitric oxide synthase
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• Function of NO
• It acts as endothelial derived releasing factor (EDRF) and cause smooth muscle relaxation. (General)
• NO functions as a vasodilator and muscle relaxant.
• It is the key molecule in the regulation of blood flow and the blood pressure.
• NO acts as inhibitor of platelets aggregation and adhesion.
• It functions as a messenger molecule of the nervous system (neurotransmitter).
• NO mediate the bacterial action of macrophages.
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