metabolism of simple and chromoproteins - biochimia.usmf.md · 1 metabolism of simple and...
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Metabolism of Simple andChromoproteins
Nitrogen turnover
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Nitrogen Balance (NB)
NB= ingested nitogen - excreted nitrogen
l Ingested nitrogen – main source – proteinsl Excreted nitrogen – main route – urinel Reflects the equilibrium of protein
metabolism – prevalence of biosynthesis ordegradation
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Nitrogen Balance (NB)
Types:1. Positive: Ingested N > excreted N2. Negative: Ingested N < excreted N3. Balanced: Ingested N ≈ excreted N
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Dietary protein recquirments
l Children (untill 13 years old ) –13-34 g/24 h
l Adolescents – (13-18 yearsold) – 34-52 g/24 h
l Healthy adults – 46-56 g/24 hl Pregnancy – 80 g/24 h
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Dietary Proteins- biological value
Depends on:1. Amino acidic
composition –essential vsnon-essentialamino acids
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Dietary Proteins - biological value
Depends on:2. ability of the organism to assimilate
the protein – digest proteins andabsorb the amino acids
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Dietary Protein Turnover
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Generalpathway of
proteindigestion
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Digestion of dietary proteins
1. Localization: stomach + small intestine;2. Necessary compounds:
– proteolytic enzymes;– HCl;– HCO3
- ;– transmembrane transporters;– local regulatiors.
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Proteolytic enzymes - Proteases
HydrolasesProteases or proteinase or peptidases
1. Endopeptidases2. Exopeptidases:
a. aminopepditasesb. carboxypeptidases
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Proteolytic enzymes
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Proteolytic enzymes
Endopeptidases1. Pepsine2. Trypsine3. Chymotrypsine4. Collagenase5. Elastase
Exopeptidases1. Aminopeptidase2. Carboxypeptidase
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Specificity of the proteolytic enzymes
Enzyme Peptide bond formed by:
Pepsin -NH2 gr. of Phe, Tyr, Trp, Leu,Asp, Glu
Trypsin -COOH gr . of Arg and Lys
Chymotrypsin -COOH gr . of Phe, Tyr, Trp
Carboxypeptidase Phe, Tyr, Trp, Arg, Lys andhydrophobic C-terminal aminoacids
Aminopeptidase N-terminal amino acids14
Specificity of the proteolytic enzymes
Enzyme Produced in : Produced:
Pepsin Stomach Non-active
Trypsin Pancreas Non-active
Chymotrypsin Pancreas Non-active
Carboxypeptidase Pancreas Non-active
Aminopeptidase Intestine Active
Dipeptidases Intestine Active15
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Activation of the proteolytic enzymes
Mechanism – partial proteolysisActivators:1. Pepsinogen – HCl, pepsin2. Trypsinogen – enterokinase or
enteropeptidase3. Chymotrypsinogen – trypsin4. Procarboxypeptidase - trypsin
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Mechanism of partial proteolysis
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Role of HCl in the digestion of proteins
l Activation of pepsinogen to pepsinl Maintenance of optimal pH for pepsinl Denaturation of dietary proteinsl Contribution to Fe2+ absorptionl Antibacterial action
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Secretion of hydrochloric acid
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Digestion of proteins in the stomachROLE OF THE CELLS
l MUCOUS CELLS - secrete mucus to protectlining from potential destructiveness of acidicgastric juice
l CHIEF CELLS - secrete digestive enzymes,mainly pepsinogen
l PARIETAL CELLS - secrete HCl and Intrinsicfactor
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Digestion of proteins in the stomach
l Entry of protein into the stomach stimulates thesecretion of the local hormone gastrin
l Gastrin stimulates secretion of pepsinogen and HCll pH – 1,0-2,0l Denaturation of proteins by HCll Activation of pepsinogen to pepsin by HCl and
active pepsinl Pepsin hydrolyzes peptide bonds on the amino-
side of Tyr, Phe, and Trpl Final products of hydrolysis - polypeptides and
oligopeptides21
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Digestion of proteins in small intestineRole of local hormones
l Secretin stimulates the pancreas to secretepancreatic juice rich in bicarbonate to neutralizethe gastric HCI
l The entry of amino acids into duodenum inducethe release of the cholecystokinin, whichstimulates secretion of pancreatic juice rich inenzymes
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Digestion of proteins in the intestinePancreatic Juice
l Is a water solution of enzymes andelectrolytes (primarily HCO3
-)
l Neutralizes acid chymeHCl + HCO3
- → Cl- + H2CO3 → H2O + CO2 ↑
l Provides optimal environment forpancreatic enzymes (pH ≈ 7,0-8,0)
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Digestion of proteins in the intestinePancreatic Juice
Enzymes are secreted INACTIVEas ZYMOGENS or PROENZYMES
1. Trypsinogen2. Chymotrypsinogen3. Procarboxypeptidase4. Proelastase
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Activation of pancreatic enzymes
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Digestion of proteins in the intestineIntestinal enzymes
The cells of the small intestine secreteactive enzymes:
Ø aminopeptidase - hydrolyze successive
amino-terminal residues
Ø dipeptidases - hydrolase dipeptides
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Digestion of proteins in the intestineFinal products
By the sequential action of proteolytic
enzymes, ingested proteins
are hydrolyzed to yield a mixture of
free amino acids
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Acute pancreatitis
In this condition:Ø the zymogens of the proteolytic enzymes are
converted into their active forms prematurely,inside the pancreatic cells →
Ø as a result, these proteolytic enzymes attack thepancreatic cell and tissue itself →
Ø causing a painful and serious destruction of theorgan, which can be fatal.
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Absorption of amino acidsmechanism I – simport with Na+
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Absorption of amino acidsmechanism II – g-glutamyl cycle
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Putrefaction of Aminoacids
1. Location – large intestine2. Mechanism – action of microorganisms3. Production:
Ø Scatol, Indol from TrpØ Crezol, Phenol from Phe and TyrØ Putrescin from ornitineØ Cadaverine from Lys
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Putrefaction of Aminoacids
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Detoxification of putrefaction products
l Location – liverl Mechanism: I step – oxidation
II step – conjugationl Oxidation – microsomal chain of oxidationl Conjugation – sulfate ion, glucuronic acid,
acetyl-, etc.
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Detoxification of Indol
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Metabolic Fates of Amino Acids
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Amino acid pool
l 30 g from the total 15 kg of proteins of theorganism (if total body mass is about 70 kg )
l Free blood amino acids – 0,35-0,65 g/l.
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General pathwaysof amino acids catabolism
1. Pathways of carboxyl group metabolism –decarboxylation
2. Pathways of amino group metabolisml Transaminationl Deamination
3. Pathways of carbon skeletons catabolism
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Pathways of carboxyl group metabolism– decarboxylation
1. α-decarboxylation – formation of biogenic amines
2. ω-decarboxylation;
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Pathways of carboxyl group metabolism– decarboxylation
3. Decarboxylation coupled with transamination
4. Decaboxylation coupled with condensation of 2molecules
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Amino acids are converted toBIOLOGICAL AMINESby α-decarboxylation
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Histamine synthesis
Substrate – HisBiological action:1. stimulation of gastric secretion;2. histaminergic action modulates sleep due to
stimulatory effects upon neurons3. suppressive action that protect against the
susceptibility to convulsion, drug sensitization etc.4. involved in immune system disorders and allergies41
GABA synthesis
GABA inhibits synaptic transmissionAntiepileptic remedy42
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Serotonin synthesisSerotonine was isolated in 1948 by Page
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Serotonin role
l neurotransmitter, allowing numerousfunctions in the human body including thecontrol of appetite, sleep, memory andlearning, temperature regulation, mood,behaviour, cardiovascular function, musclecontraction, endocrine regulation anddepression.
l a powerful vasoconstrictor in blood44
Catecholamines synthesis
l Tyrosine gives rise to the catecholamines:dopamine, norepinephrine (noradrenaline)and epinephrine (adrenaline)
l Levels of catecholamines are correlated withblood pressure
l The neurological disorder Parkinson's diseaseis associated with an underproduction ofdopamine
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Biological Aminesl overproduction of dopamine in the brain is
associated with psychological disorders such asschizophrenia
l low serotonin levels are associatedwith obsessive-compulsive tendenciesor seasonal depression
l histamine excess can be manifest as asthma,vasomotor rhinitis, allergic skin disorders withpruritis, excess stomach acid production, saliva,tears, thin nasal and bronchial secretions, andcertain types of vascular headaches
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Inactivation of biological amines
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Common metabolic pathways of theamino- group
1. Transamination2. Deamination:
a. directb. indirect
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Transamination reaction
l Removal of the α-amino groups from the α-L-aminoacids, by →
l Transfer to the α-keto carbon atom of an α-keto acid,mainly α-keto glutarate
l Enzymes – aminotransferases, class transferasesl Goal of transamination – collection of the amino
groups from different amino acids in only one –L-glutamate
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Transamination reaction
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Vitamine B6
Pyridoxine Pyridoxal Pyridoxamine
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Vitamine B6
Pyridoxal Pyridoxaminephosphate phosphate
(PALP) (PAMP)
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PALP and PAMP (deriv. Vit B6)
l covalently bound to the E through ε-aminogroup of Lys
l intermediate carrier of amino groups duringtransamination by →
l reversible transformations between pyridoxalphosphate (PALP), which accept the aminogroup, and pyridoxamine phosphate (PAMP),which donates its amino group to the α-ketoacid
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PALP –coenzymeof amino-transfe-rases
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Transamination of alanine
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Transamination of aspartic acid
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Diagnostical value ofaminotransferases
Myocardial infarction
Ø aminotransferases, among other enzymes, leakfrom the injured heart cells into the bloodstream
Ø increased concentration in the blood serum of AsATØ increased concentration of other heart enzymes
creatine kinase (CK), lactate dehydrogenase(LDH) and proteins (myoglobin, troponins etc.)
Ø can provide information about the severity and thestage of the heart damage
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Diagnostical value of aminotransferasesin liver diseases
Acute viral hepatitis: ALT – 25-50 times ↑
AST – 15-30 times ↑
maximal values - 2 weeks of the jaundiceperiode
Type A – high values from the beginning andrapidly decrease
Type B – moderate progresive increase during1-2 months59
Deamination
Removal of -NH2 group from the amino acidin form of ammonia
Types:1. Direct2. Indirect
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Direct deamination
l oxidativ+½ O2
R-CH-COOH → R-C-COOH + NH3׀ ׀׀NH2 O
l intramolecular
R-CH2-CH-COOH → R-CH=CH-COOH + NH3׀NH2
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Direct oxidative deaminationof amino acids
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Non-oxidativedirect deamination of Serine
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Non-oxidativedirect deamination of treonine
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Histidine non-oxidative direct deamination
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Direct deamination of glutamic acid
E – glutamate dehydrogenase
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Direct deamination of glutamic acid
l L-glutamate dehydrogenase (Mr 330,000).l Located in mitochondrial Co-enzymes - NAD+ or NADP+
l Final products: ammonia – detoxificationNADH.H+ – oxidationα-keto glutarate – oxidation
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Regulation of Glu deamination
l glutamate dehydrogenase is an allostericenzyme
l positive modulator – ADPl negative modulator – GTP
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Indirect deamination of aminoacids
2 steps:I step – transamination – goal: colection of
the -NH2 groups in the structure of GLUII step – direct deamination of Glu – goal:
removal of -NH2 group in form of ammonia
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Indirect deamination of aminoacids
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Indirect deamination of aminoacids
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Sources of blood ammonia
l Amino acids deaminationl Biogen amine detoxificationl Catabolis of nitrogen basesl Absorption from large intestine
(putrefaction of amino acids)
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Ammonia toxicity
l Liver diseases →l Disorders of the urea cycle →l Increased concentration of ammonia
in the blood (hyperammoniemia)
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Ammonia toxicity
Detoxification of the excess ammoniadisturbes the energetic metabolism due to:Ø reductive amination of α-keto glutarate toGlu – depletes cellular NADH and α-ketoglutarate, required for ATP productionØ conversion of Glu to glutamine byglutamine synthetase – depletes ATP itself
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Brain ammonia toxicity
l ammonia passes brain blood barrierl disorders or absence of aerobic oxidative
phosphorylation and TCA cycle activitydamage neural cell
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Brain ammonia toxicity
l Increased ammonia leeds to glutamineformation from Glu
l this depletes glutamate stores which areneeded in neural tissue for neurotransmitterssynthesis (glutamate itself and GABA)
l Therefore, reductions in brain glutamatedisturb energy production as well asneurotransmission
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Mechanisms of ammonia detoxification
l Temporary detoxification – biosynthesisof Asn and Gln
l Final detoxification:a) formation and renal excretion ofammonia saltsb) synthesis of urea
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Mechanismof Asn and Gln biosynthesis (1)
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Mechanismof Asn and Gln biosynthesis (2)
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Biological role of Asn and Gln
l Transport of NH3 from different tissues tothe site of excretion (kidneys) and the siteof final detoxification (liver)
l Asn and Gln are nontoxic, neutralcompound that pass through cellmembranes, whereas aspartate andglutamate, which bears a net negativecharge, cannot.
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Ammonia release from Asn and Gln
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Ammonia release from Asn and Gln
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Urea cycleKrebs-Henseleit cycle
l Role – final and complete detoxification ofammonia
l Final product – ureal Location – hepatocytes – partial
mitochondria, partial cytosoll Energy consumption – 3 mol of ATP or 4
high energetic bondsl Sources of NH2 groups: NH3 and Asp
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Urea cycle
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Carbamoyl phosphate synthetasereaction of urea synthesis
E - Carbamoyl phosphate synthetase I (CPS I)mitochondrial matrix enzyme
is positively allosteric regulated by N-acetylglutamate
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1st reaction of the urea cycle
E – carbamoilphosphate ornitine transferaseCitruline transported to cytoplasm by specifictransporter; mechanism – antiport with ornithine
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2nd reaction of the urea cycle
E – argininosuccinate synthetaseConsumed – 1 ATP=2 high energetic bonds
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3rd reaction of the urea cycle
E – arginonisuccinate lyase
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4th reaction of the urea cycle
E - arginase
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Regulation of the activity of the urea cycle
l Long term – gene level – biosynthesis ofthe enzymes; regulating factor – ammoniaconcentration in the blood
l Short term – allosteric regulation –carbamoylphosphate synthetase; possitivemodulator – N-acetylglutamate
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Connection of the urea and TCA cycles
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Metabolism of the carbon skeletonsof the amino acids
Carbon skeletons – the α-keto acids producedduring the deamination of the amino acids
Amino acids are degraded to:Ø pyruvate,Ø α-ketoglutarate,Ø succinyl-CoA,Ø fumarate,Ø oxaloacetate,Ø acetyl-CoA,Ø acetoacetate.92
Metabolism of the carbon skeletonsof the amino acids
Utilisation of the carbon skeletons:
1. enter into the Krebs cycle and are oxidased
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Metabolism of the carbon skeletonsof the amino acids
Utilisation of the carbon skeletons:
2. are transformed into glucose – glucogenicamino acids
3. are transformed into ketone bodies –ketogenic amino acids
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Glucogenicand
ketogenicamino acids
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Glucogenic amino acids
Carbon skeletons of glucogenic amino acidsare degraded to:
w pyruvate, orw intermediates of Krebs Cycle:
a. 4-C (succinil, succinate, fumarate or OA)b. 5-C (α-ketoglutarate).
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Glucogenic amino acids
1. are the major carbon source forgluconeogenesis when glucose levels arelow.
2. can be converted to glycogen or or fattyacids for energy storage.
3. can be catabolized for energy
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Ketogenic amino acids
Carbon skeletons of ketogenic amino acids aredegraded to:w acetyl-CoA, orw acetoacetate.Can be converted to:1. ketone bodies2. fatty acidsCan be catabolized for energy in Krebs Cycle
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Metabolism of individualamino acids
Tetrahydrofolic acid
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Folic acid (or vit. B9 or vit. Bc)
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Functions of the Tetrahydrofolic Acid
Ø Carry and transfer one carbon units fromcatabolic reaction to biosynthetic one
Ø The one carbon units are:• methyl (-CH3)• methylene (-CH2-)• methenyl (=CH-)• formyl (-COH)• formimino (-CO=NH)• etc.10
4
One carbon units attached to theactive center of FH4
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Folic acid - RDAl RDA (recommended daily allowance) for adults –400 μgl RDA for pregnant women – 600 μg.l the best sources for folic acid:
ü beef liver;ü baked beans,ü raw spinach,ü green peas,ü broccoli,ü avocado,ü peanuts,ü wheat germ,ü tomato juice,
ü orange juice.106
Functions of the Tetrahydrofolic Acid
107
Metabolism of Gly and Ser
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Metabolism of Gly and Ser
1. Non-essential amino acids– Gly is produced from Ser and Tre– Ser is produced from Gly and 3-phosphoglycerate
2. Glucogenic amino acids
109
Metabolism of Gly and Ser
Interconversion of Gly and Ser
110
Biosynthesis of serine
111
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Serine metabolism
112
Glycine metabolism
113
Metabolism of Glu
114
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Metabolism of Asp
115
Lys METABOLISM
Lys – essential amino acid
116
Lysinecatabolism
117
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Pro metabolismPro biosynthesis
http://themedicalbiochemistrypage.org/images/ornithine-proline.jpg
118
Pro hydroxylation
119
Metabolism of cromoproteins
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Cromoproteins
l Hempoproteinsl Flavoproteins
121
Hempoproteins
l Hemoglobinl Mioglobinl Cytocromesl Catalasel Peroxidasel Etc.
122
Hemoglobin
123
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Hemoglobin
124
Heme synthesis
1. Globin synthesis – ribosomes2. Hem synthesis:
a. heme is synthesized in all tissuesb. the principal sites of synthesis are:– erythroid cells (≈85%)– hepatocytes (accounting for nearly all the
rest of heme synthesis)125
Heme synthesis
– 1st and the last 2 reactions – in themitochondria
– the rest – in the cytosol
126
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Heme synthesis
127
Heme synthesis
128
Heme synthesis
129
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Heme synthesis
130
Heme synthesis – regulation
1. transcription of ALA synthase (1 reaction) –controlled by Fe2+-binding elements →prevents accumulation of porphyrinintermediates in the absence of Fe2+
2. ALA synthase is inhibited by heme andhemin
131
Disorders of Heme synthesis - porphyrias
132
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Hemoglobincatabolism
133
http://classconnection.s3.amazonaws.com/591/flashcards/887591/jpg/heme1322966709022.jpg
134
Conjugated bilirubin
135
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136
137
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Differential diagnosis of jaundice
139