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141 Cards in this Set
- Front
- Back
where is haem synthesized
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bone marrow (85%) and liver
|
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steps of haem synthesis
|
synthesis of:
1. ALA (aminolevulinic acid) 2. PBG (porphobilinogen) 3. uroporphyrinogen 4. coproporphyrinogen 5. protoporphyrinogen III, IX, heme |
|
ALA synthesis
|
glycine + succinyl CoA ---ALA SYNTAHSE[PLP]----> AKA (amino ketoadipic acid) + CoAsh
AKA ----ALA SYNTHETASE[B6, PO4]---> ALA + CO2 |
|
Site of ALA synthesis
|
mitochondria
|
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what inhibits ALA synthesis
|
hematin and heme
|
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PBG synthesis
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2 ALA -----ALA DEHYDRATASE----> PBG + 2H2O
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site of pbg synthesis
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cytoplasm
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what inhibits PBG synthesis
|
lead
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uroporphyrinogen synthesis
|
4 porphobilinogen ---UROPORPHYRINOGEN I SYNTHASE ---> uroporphyrinogen I + 4 NH2
uroporphyrinogen I -----UROPORPHYRINOGEN III COSYNTHASE---> Uroporphyrinogen III |
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synthesis of coproporphyrinogen
|
uroporphyrinogen III ----DECARBOXYLASE----> coproporphyrinogen III + 4CO2
|
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site of coproporphyrinogen synthesis
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cytoplasm
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protoporphyrinogen III synthesis
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coproporphyrinogen III -----COPROPORPHYRINOGEN OXIDASE---> protoporphyrinogen III + 2CO2
|
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site of protoporphyrinogen III synthesis
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mitochondria
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protoporphyrin IX synthesis
|
protoporphyrinogen III -----PROTOPORPHYRINOGEN OXIDASE---> protoporphyrin III + 6H
protoporphyrin III is protoporphyrin IX |
|
heme synthesis
|
Protoporphyrin III ----HEAM SYNTHASE----> heam
|
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regulation of haem synthesis
|
1- haem and haematin repress the synthesis of ALA synthase [allosteric inhibitor]
2- glucose/proximal metabolite INHIBIT 3- pantothenic acid/B6 deficiency INHIBIT 4-mercury/lead INHIBITS ALA dehydratase |
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how are RBCs broken down
|
reticuloendothelial system
|
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haem catabolism
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haem ---HAEM OXYGENASE[O2,NADPH]--> biliverdin + CO + Fe3+
biliverdin ---BILIVERDIN REDUCTASE---> bilirubin [bilirubin + albumin] leave RES to enter liver. |
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where does heam catabolism take place
|
microsomal fraction of reticuloendothelial cells
|
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bilirubin metabolism
|
1. liver takes up bilirumin, removes it from albumin. it is then taken up at the sinusoidal surface of hepatocytes by CARRIER MEDIATED SATURABLE SYSTEM
2. Conjugation: bilirubin + 2 glucuronic ----UDP GLUCURONYL TRANSFERASE---> bilirubin diglucuronide (sol) 3. Secretion: conjugated bilirubin is secreted by active transport into bile |
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how are glucuronates removed?
|
in the large intest, special bacterial enzymes (alpha? glucuronidase) .
the pigment is reduced by fecal flora into urobilinogens which are normally oxidised to urobilin (colored) and are excreted in urine, faeces |
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cause of physiological jaundice in newborns
|
inability of neonatal liver to form bilirubin glucuronide at a rate comparable to that of bilirubal production
|
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cause of congenital familial non-hemolytic jaundice
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deficiency of UDP glucuronyl transferase enzyme --> accumulation of unconjugated bilirubin in the blood which is toxic to the brain and leads to mental retardation
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disorders of haem metabolism
|
A- BIOSYNTHESIS (porphyrias)
1. congenital 2. acquired (toxic) B- CATABOLISM (hyperbilirubinemia)(jaundice) 1. prehepatic (hemoltyic) 2. hepatic 3. post hepatic (obstructive) |
|
the clinical signs and symptoms of porphyrias result from either..
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a) deficiency of metabolic products beyond the enzymatic block of Hb synthesis
b) accumulation of metabolites before the block |
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cause of acquired porphyrias
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exposure to toxic compounds eg hexachlorobenzene and heavy metals eg lead
they inhibit ferrochelatase and ALA dehydratase. |
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symptoms of acquired porphyrias
|
severe anaemia, accumulation of ALA and coproporphyrin III in urine
|
|
treatment of porphyrias
|
1. avoid exposure to sunlight
2. injection of hemin 3. antioxidants and beta carotene |
|
when does hyperbilirubinemia/jaundice occur
|
hyperbilirubinemia occurs if plasma bilirubin levels exceed its normal value (1mg/dl) while jaundice (yellow discoloration of skin and sclera of eyes) is manifested at levels above 2mg/dl
|
|
forms of bilirubin in plasma
|
a) UNCONJUGATED (indirect reacting van den bergh= bilirubin albumin complex)
main form, present normally in plasma increases in hemolytic anaemia b) CONJUGATED (direct reacting van den bergh = bilirubin diglucuronide) escapes from liver to systemic blood |
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characteristics of prehepatic jaundice
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excessive destruction of RBCs
characterized by elevation of total serum bilirubin and indirect bilirubin with dark urine and stool SGPT SGOT usually normal, bile salts absent from urine |
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causes of prehepatic jaundice
|
1) RH incompatibility
2) chronic hemolytic anemia 3) mismatched blood transfusion |
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when does physiological jaundice of newborns occur and why?
|
- occurs 3rd day after birth
- due to reduced activity of UDP-glucuronyl transferase enzyme -usually relieved spontaneously w/o residual damage |
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characterizations of hepatic jaundice
|
- elevated total serum bilirubin (both direct and indirect) with dark color of urine and stool
- liver functions are usually deteriorated - elevated serum enzymes (SGPT, SGOT, gamma GT) -bile salts may be present/absent in urine |
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causes of hepatic jaundice
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usually due to damage of hepatic cells due to
1. infections: hepatitis ABCD 2. toxic agents and chemicals eg CCL4, anesthetics |
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cause of post hepatic jaundice
|
obstruction of common bile duct (by stone or cancer in head of the pancreas)
|
|
characterizations of post hepatic jaundice
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- elevated total serum bilirubin especially direct bilirbuin
- dark color of urine and whitish (clay colored) stool - usually normal liver functions almost normal SGPT, SGOT, gamma GT - elevated serum alkaline phosphate - bile salts in urine |
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degradation of nucleoproteins
|
Nucleoproteins --> nucleic acids
by: proteolytic enzymes in the intestinal tract |
|
degradation of nucleic acids
|
Nucleic acids --> mononucleotides
by: ribonucleases, deoxyribonucleases, polynucleotidases |
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degradation of mononucleotides
|
mononucleotides --> nucleosides
by: nucleotidases, phosphatases |
|
fate of nucleosides
|
either :
a) absorbed or b) further degraded by intestinal nucleosidase to purine bases, pyrimidine bases and pentoses |
|
dietary purines and pyrimidines are largely..
|
catabolized in the intestinal mucosal cells
|
|
why are pentoses not utilized in the body
|
due to the absence of specific pentose kinase in the human body
|
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how can nucleotides be synthesized
|
a) de novo synthesis
b) salvage pathways that allow the reuse of the performed bases resulting from normal cell turnover |
|
sources of atoms in the purine ring
|
aspartic acid (N1)
glycine (C4, C5, N7) glutamine (N3, N9) CO2 (C6) derivatives of tetrahydrofolic acid (C2,C8) + other |
|
how is the purine ring constructed
|
by a series of reactions that add the donated carbons and nitrogens to a preformed ribose-5-phosphate obtained from the hexose monophosphate shunt
|
|
first step of purine biosynthesis
|
1. transfer of pyrophosphate from ATP to C1 of ribose 5 phosphate
----5-PHOSPHORIBOSYL 1-PYROPHOSPHATE SYNTHASE---> 5-phosphoribosyl 1-pyrophosphate (PRPP) |
|
PRPP is an intermediate in ..
|
-synthesis of :
purines, pyrimidines, NAD+, NADP+ -purine salvage pathway |
|
second step of purine biosynthesis
|
displacement of pyrophosphate from PRPP by the amide nitrogen of glutamine---PRPP GLUTAMYLAMIDOTRANSFERASE--->5-phosphoribosylamine.
this involves the inversion of configuration at C1, and forms beta-N-glycosidic bond. |
|
how is IMP converted to AMP
|
IMP + aspartate ----ADENYLSUCCINATE SYNTHETASE---> adenyl succinate
adenylsuccinate ------ADENYLOSUCCINASE----> AMP + fumerate |
|
how is IMP converted to GMP
|
IMP + H2O -------IMP DEHYDROGENASE[NAD]---> XMP
XMP -----[glutamine --> glutamate, ATP ]---> GMP |
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how are AMP and GMP converted to their respective nucleoside di and triphosphates?
|
succesive phosphoryl transfer from ATP, catalyzed by nucleoside monophosphate kinase and nucleoside diphosphate kinase respectively
|
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how are deoxyribonucleotides formed
|
by direct reduction at 2' carbon in the ribose moiety of the corresponding nucleotide. This occurs only after the conversion of the nucleotide to its nucleoside diphosphate
This reaction is catalyzed by the ribonucleotide reductase complex. reduction requires thioredoxin (protein cofactor), thioredoxin reductase (flavoprotein) , NADPH |
|
how does tissue incapable of de novo synthesis obtain purines?
|
the mammalian liver provides purines in the form of bases or their nucleosides to be utilized by other tissue.
eg human brain has very low levels of PRPP aminotransferase (depends in part on exogenous purines) Erythrocytes and polymorphnuclear leukocytes cant synthesize 5-phosphoribosylamine so use exogenous purines to form nucleotides |
|
regulation of purine biosynthesis
|
a) concentration of PRPP intracellularly
b) inhibition of tetrahydrofolate compounds synthesis c) PRPP amidotransferase d) 6- mercaptopurine inhibits reactoions no. 13, 14 e) AMP and GMP |
|
how does the concentration of PRPP intracellularly regulate purine synthesis
|
conc determines the overall rate of purine synthesis. PRPP synthesis depends on availability of ribose-5-phosphate and activity of PRPP synthetase.
PRPP synthetase is sensitive to both phosphate conc and purine ribonucleotides that act as allosteric regulators |
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how does inhibition of tetrahydrofolate formation regulate purine synthesis
|
C2 and C8 are derived from N5, N10 methenyl and N10 formyltetrahydrofolate. inhibition of tetrahydrofolate synthesis can block purine synthesis.
|
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how does PRPP amidotransferase affect purine synthesis
|
PRPP amidotransferase is subject to feedback inhibition by purine nucleotides (AMP, GMP)
PRPP conc is a +ve stimulateor of amidotransferase |
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how do AMP and GMP regulate purine synthesis
|
AMP feedback regulates adenylosuccinate synthetase
GMP feedback inhibits IMP dehydrogenase |
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what is purine salvage pathway
|
purines that result from normal turnover of cellular nucleic acids and not degraded can be reconverted into nucleoside triphosphate and used by the body
requires less energy than denovo |
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where does the salvage pathway occur
|
primarily in extrahepatic tissues
|
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most imp mechanism of purine salvage pathway
|
phosphoribosylation of a free purine base by PRPP forming purine 5-mononucleotide
|
|
what catalyzes prpp dependnet phosphoribosylation of purines
|
adenine phosphoribosyltransferase (converts adenine to AMP)
hypoxanthine guanine phosphoribosyltransferase (converts hypoxanthine/guanine to IMP/GMP) |
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second salvage mechanism for purines?
|
direct phosphorylation of purine ribonucleoside by ATP using kinase enzyme
|
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what is the end product of purine catabolism
|
uric acid
|
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steps of purine catabolism
|
A)
adenosine -------ADENOSINE DEAMINASE [H2O]------> Inosine + NH4 Inosine -----PURINE NUCLEOSIDE PHOSPHORYLASE[Pi]-----> hypoxanthine + ribose-1-phosphate Hypoxanthine ----XANTHINE OXIDASE[H2O + O2]---->xanthine +H2O2 B) Guanosine -----PURINE NUCLEOSIDE PHOSPHORYLASE[Pi]----> Guanine + ribose-1-phosphate Guanine -----GUANASE---> Xanthine + NH3 C) Xanthine ----XANTHINE OXIDASE[H2O+O2]---> uric acid + H2O2 |
|
Clinical disorders of purine metabolism
|
***HYPERURICAEMIA***
1) Primary Hyperuricaemia a) Abnormalities of purine metabolism b) Abnormalities of other metabolic pathways 2) Secondary Hyperuricaema ***GOUT*** |
|
What is hyperuricaemia
|
characterized by excessive amount of uric acid in the blood
many cases due to accelerated production of uric acid, secondary to degradation of unusually large quantities of purines |
|
abnormalities in purine metabolism
|
1) PRPP SYNTHETASE
mutant forms which are not subject to allosteric regulation by Pi or to feedback inhibition intracellular conc of PRPP elevated --> increased phosphoribosylamine formation--> increased purine production --> increased catabolism, increased urate 2) PARTIAL HGPRtase deficiency decrease activity of hypoxanthin/guanine that can be salvaged --> overproduction of purine nucleotide ,PRPP increased cuz its not consumed via salvage pathway |
|
Abnormaltiies in other metabolic pathways of purine
|
1) G-6-PHOSPHATASE DEFICIENCY
glycogen storage disease type 1, von gerks lack of conversion of G6P to glucose --> increased HMS activity --> increased R5P levels ---> increased PRPP levels --> increased purine nucleotides denovo synthesis 2)INCREASED GLUTATHIONE REDUCTASE ACTIVITY glutathione reductase generates NADP which is required to drive the first two reactions of HMS ---> increased PRPP |
|
causes of secondary hyperuricaemia
|
1) some diseases eg malignancy which enhance tissue turn over
also in case of tissue breakdown (after treatment of large malignant tumors by radiotherapy or cytotoxic drugs) 2) decreased rate of urate excretion |
|
What is gout
|
- metabolic disease
- characterized by excessive amount of uric acid in blood due to the previously mentioned causes (duh) - sodium urate levels exceed solubility levels (M: 3-7 mg/dL , F: 2-6 mg/dL) - sodium urate crystals form in soft tissues and joints forming deposits --> inflammatory reaction esp in big toe - sodium urate may be precipitated in the kidney tubules --> kidney stones |
|
Principal treatments of hyperuricaemia
|
1. reducing dietary purine intake
2. increasing renal excretion of urate with uricosuric drugs eg PROBENCID. fluid intake must be kept high. 3. reducing urate production using drugs which inhibit xanthine oxidase activity eg ALLOPURINOL (isomer of hypoxanthine) 4. COLCHICINE which has an anti inflammatory effect in acute gouty arthritis, does not affect urate metabolism |
|
effect of allopurinol treatment?
|
lower uric acid levels in vivo which result from increased rate of purine catabolism
allopurinol is oxidised by xanthine oxidase to alloxanthine. this product is a very effective inhibitor of xanthine oxidase --> decreases formation of uric acid while increasing the levels of hypoxanthine and xanthine excreted. hypoxanthine and xanthine are more soluble and do not ppt as easily as urate |
|
sources of atoms for the pyrimidine ring
|
carbamoyl phosphate and aspartic acid
|
|
steps of pyrimidine nucleotides synthesis
|
CAP
CAA DHOA OA OMP UMP UDP UTP CTP UDP --> dUDP --> dUMP--> TMP |
|
where does catabolism of pyimidines occur? what are the end products?
|
LIVER
CO2, NH3, beta alanine , beta aminoisobutyrate |
|
disorders of pyrimidine metabolism
|
orotic aciduria
caused by deficiency of : 1. orotate phosphoribosyltrasferase 2. orotodylic acid decarboxylase orotic acid accumulates in blood and is excreted in urine |
|
manifestations of orotic aciduria
|
growth retardation
mental retardation anaemia excretion of large amounts of orotic acid and dihydroorotic acid in urine |
|
treatment of orotic aciduria
|
1) ORAL URIDINE AND CYTIDINE
will be salvaged into the corresponding nucleotide, thus bypassing the defective pathway, providing the growing tissue by their demand of nucleotides. overcomes retarded growth and repairs anaemia. 2) PERFORMED UTP inhibits CPSII thus shutting down orotic acid synthase, decreasing its level in blood and urine |
|
describe water soluble vitamins
|
- members of B complex and vitamin C
- polar hydrophilic - readily excreted --> toxicities are rare, deficiencies are common - most are coenzymes, or are converted to coenzymes which are utilized for energy generation or hematopoieses |
|
b complex vitamins
|
1. thiamin (Vitamin B1)
2. riboflavin (vitamin B2) 3. Niacin (nicotinic acid, nicotinamide) (vitamin b3) 4. pantothenic acid (vitamin b5) 5. vitamin b6 (pyridoxal, pyridoxine, pyridoxamine) 6. biotin 7. lipoic acid (thioctic acid) 8. folic acid (pteroylglutamic acid/ folacin) 9. vitamin b12 (cobalamin) |
|
chemistry of thiamin
|
consists of a substituted pyramidine joined by a methylene bridge to a substituted thiazole
|
|
requirements of thiamin
|
1-2 mg/day
|
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sources of thiamin
|
PLANT:
whole grains, yeast, beans, peas, bran ANIMALS: liver, heart, kidney, milk |
|
functions of thiamin
|
production of TPP
thiamin -------THIAMIN DIPHOSPHOTRANSFERASE---> thiamin diphosphate (TPP) site: brain, liver |
|
importance of TPP
|
it is a coenzyme transferring an activated aldehyde unit in the following reactions:
1. oxidative decarboxylation of alpha keto acids (pyruvate etc see book) 2. transketolase reactions (eg PPP) 3. acetylcholine synthesis |
|
causes of thiamin deficiency
|
1. antithiamine factors
2. alcoholism 3. low intake, malabsorption, defective phosphorylation to TPP |
|
how do antithiamine factors cause thiamin deficiency
|
- enzymes present in the VISCERA of shell fish and many microorganisms
- cause CLEAVAGE of thiamin --> pyrimidine & thiazole rings ("thiaminases") - cause an isolated thiamin deficieny |
|
how does alcoholism cause thiamin deficiency
|
chronic alcoholism gives mod thiamin deficiency
called WERNICKE KORSACOFF SYNDROME |
|
cause of beriberi (severe thiamin deficiency)
|
carbohydrate rich/low thiamin diets
types: dry beriberi wet beriberi |
|
characteristics of dry beriberi
|
advanced neruomuscular symptoms including atrophy and weakness of the muscles and peripheral neuropathy
|
|
characteristics of wet beriberi
|
advanced neruomuscular symptoms including atrophy and weakness of the muscles and peripheral neuropathy
+ oedema |
|
chemistry of riboflavin (vitamin b2)
|
a heterocyclic isoalloxazine (flavin) ring attached to D ribitol
|
|
functions of riboflavin
|
produces FMN and FAD
riboflavin -------> FMN FMN ------------> FAD occurs in most tissues FMN and FAD serve as prosthetic groups of oxidoreductase enzymes (flavoprotein enzymes) |
|
functions of flavoprotein enzymes
|
1. oxidative decarboxylation of alpha keto acids
[ FAD coenzyme of dihydrolipoyl dehydrogenase) 2. oxidative degradation of fatty acids (FAD is the prosthetic group of acyl CoA dehydrogenase) 3. oxidative deamination of alpha amino acids [L amino acid oxidase, prosthetic group: FMN D amino acid oxidase pp:FAD] 4. Dehydrogenation of succinic acid in CAC |
|
how are flavoproteins reduces?
|
undergo reversible reduction of the isoalloxazine ring to yield FMNH2 and FADH2
|
|
manifestations of riboflavin deficiency
|
cheilosis
angular somatitis glossitis seborrhea (dermatitis) occular disturbances (photophobia) vascularization of cornea |
|
chemistry of nicotinic acid
|
monocarboxylic acid derivative of pyridine
|
|
sources of nicotinic acid
|
some could by synthesized by tryptophan by plants n most animals in a pathway that requires PPi but is usually insufficient so dietary sources of niacin and tryptophan are needed:
- food containing nicotinic acid eg B1 - tryptophan containing proteins eg meat [60 mg tryptophan --> 1 mg nicotinic acid] |
|
functions of niacin
|
nicotinate (a form of niacin) is required for the synthesis of NAD and NADP
|
|
importance of NAD and NADP
|
coenzymes of many oxidoreductase enzymes
generally NAD dehydrogenases are for oxidoreduction reactions and NADP dehydrogenases are for reductive synthesis refer to page 231 for a completely useless summary of enzymes that use each |
|
manifestations of niacin deficiency
|
PELLAGRA
Dermatitis, Diarrhea, Dementia seen in skin areas exposed to sunlight --> pigmentation and thickening of the skin neurological symptoms: start by nervous disorders and mental disturbances, dementia in latter stages. |
|
pellagra caused by/associated with?
|
- patients with severe malabsorption problems
- malignant carcinoid syndrome - Hartnup disease - elderly on very restricted diet |
|
chemistry of pantothenic acid
|
amide of pantoic acid and beta alanine
|
|
functions of pantothenic acid
|
active pantothenic acid is present in COA and ACP
|
|
function of COA and ACP
|
thiol group acts as a carrier of acyl radicals in enzymatic reactions involved in:
1- FA oxidation (coash) and synthesis (ACP) 2- oxidative decarboxylation of alpha ketoacids 3- acetylation reactions eg * formation of acetylcholine [acetyl radical attached to choline at the carbonyl end (head reaction)] * formation of citric acid [acetyl radical is attached to oxloacetate at the methyl end (tail reaction)] 4- cholesterol synthesis |
|
deficiency of pantothenic acid
|
no evidence of it existing since its so widespread in natural food
most symptoms mimic those of other vitamin b deficiencies. loser. |
|
chemistry of pyridoxine (vitamin b6)
|
consists of 3 pyridine derivatives: pyridoxine, pyridoxamine, pyridoxal
all are naturally occuring |
|
functions of vitamin b6
|
absorbed from the intestine
most enzyme contain pyridoxal kinase which catalyzes the phosphorylation by ATP to their respective enzymes |
|
functions of pyridoxine coenzymes
|
only pyridoxal phosphate and pyridoxamine phosphate are active as coenzymes
functions: 1. transamination reactions 2. decarboxylation reactions of amino acids so it is required for synthesis of some neurotransmitters 3. coenzyme for non oxidative deamination of serine and threonine by dehydratases 4. threonine aldolase reaction 5. synthesis of delta amino levulinic acid, a precursor of heme 6. generation of niacin from tryptophan [hence pellagra freq accompanies pyridoxine deficiency.. think kynureninase] 7. biosynthesis of sphingosine from serine and palmitoylcoA 8. pyridoxal phosphate is an essential component of glycogen phosphorylase ie energy production |
|
manifestations of deficiency of vitamin b6
|
- peripheral neuropathy and convulsions
- anaemia |
|
synthesis of neurotransmitters using vit b6 coenzymes
|
5 hydroxytryptophan -------[PLP]-----> pyridoxal-P-5-hydroxytryptamine (serotonin) + CO2
Histidine ------[PLP]----> histamine (pyridoxamine-P) + CO2 Glutamate ----[PLP]----> GABA + CO2 Dopa ---[PLP]----> CO2 + dopamine -----> adrenaline & noradrenaline |
|
chemistry of biotin
|
heterocyclic sulphur containing vitamin
consists of fused imidazole and thiophene rings |
|
function of biotin
|
active form = BIOCYTIN
formed by holocarboxylase synthase this binds biotin to a lysine residue in the enzyme itself |
|
funciton of biocytin
|
imp for carboxylases eg
1. acetyl CoA carboxylase acetyl coA --> malonyl coA synthesis of FA 2. pyruvate carboxylase pyruvate ----> oxaloacetate gluconeogenesis |
|
cause of a deficiency of biotin
|
in animals: oral antibacterial drugs which reduce intestinal flora (srsly duh)
in HUMANS: low biotin diet containing heat labile protein AVIDIN which bins biotin in a nondigestible form preventing its absorption |
|
symptoms of biotin deficiency
|
fine scaly desquamation of the skin
anaemia anorexia nausea |
|
chemistry of lipoic acid
|
6,8-dithio-octanic acid
ie sulphur containing vitamin 2 interconvertable forms: a. oxidised form with a cyclic disulfide b. reduced open chain form "dihydrolipoic acid" with two SH groups at the 6 and 8 position |
|
sources of lipoic acid
|
many biological materials eg
yeast, liver, red meat also potatoes, beets, spinach, carrots, sweet potatoes |
|
functions of lipoic acid
|
1. coenzyme in the oxidative decarboxylation of pyruvate and other alpha keto acids (acyl carrier and hydrogen carrier)
2. potent antioxidant in the body cuz it plays a role in getting rid of free radicals |
|
hematopoietic water soluble vitamins
|
1. folic acid
2. cobalmin (vitamin B12) |
|
chemistry of folic acid (folacin = pteroyl glutamic acid)
|
formed of pteridine nucleus (bicyclic nitrogenous compound), amino benzoic acid (PABA) and glutamic acid
animal cells are not capable of synthesizing PABA or of attaching the first glutamate to the pteroic acid, but bacteria and plants can, thus animals require folic acid in their diet |
|
sources of folic acid
|
major source: leafy vegetables
other: yeast, cauliflower, liver, kidney |
|
functions of folic acid
|
formation of imp coenzyme tetrahydrofolic acid (FH4)
this is accomplished by folic acid reductase enzyme that needs NADPH+H+ (reduced COII) as a H donor FH4 (???) folate is the coenzyme for one carbon metabolism the "one carbon" moiety carried on FH4 may be : methyl, methylene, formyl, or formimino moiety. |
|
sources of the one carbon group
|
1. beta carbon of serine (major source)
2. formimino group of formimino glutamate (produced during histidine catabolism) 3. glycine 4. formate (eg intermediary metabolism of tryptophan through kynurenine pathway) |
|
functions of the one carbon group
|
various one carbon tetrahydrofolate derivatives are used in the biosynthetic reactions eg
1. synthesis of some amino acids eg glycine, serine, methionine, histidine 2. purine biosynthesis (formation of carbon 2 and carbon 8 of purine ring) coenzyme for formyl transferase 3. synthesis of deoxythymidylic acid (dTMP) coenzyme for thymidylate synthase |
|
types of folate deficiency
|
types:
a. true (primary) b. secondary to B12 deficiency |
|
manifestations of folate deficiency
|
1. MACROCYTIC ANAEMIA
associated with megaloblastic changes in bone marrow Inhibition of DNA synthesis due to decreased availablity of purines and dTMP, slows down the maturation of RBCs, causing production of large rbcs with fragile membranes 2. glossitis and gastrointestinal disturbances |
|
folic acid antagonists
|
= substances used in treatment of malignant diseases (cancer) eg methotrexate (amethopterin) and aminopterin.
They act by blocking synthesis of nucleic acids in malignant cells by preventing the reduction of folic acid to tetrahydrofolic acid |
|
chemistry of cobalamin (vit b12)
|
two components:
1. central position of the molecule (corrin ring) consists of 4 reduced and extensively substituted pyrrole rings. it is similar to porphyrin but differes in that pyrrole rings A and D are joined directly rather than through a methane bridge. coordinated to the four inner nitrogen atoms of the corrin ring is an atom of cobalt. 2. 5,6-dimethyl benzimidazole riboside: its nitrogen atom is coordinately bound to cobalt and at the other end from the ribose moiety through phosphate and amino propanol to a side chain on ring IV of the tetrapyrrole nucleus cobalt is in a coordination state of six. in the remaining position it is coordinated to one of: cyanide(CN), hydroxy (OH), or 5-deoxy adenosine to give: cyanocobalmin hydroxycobalmin methyl cobalmin 5-deoxyadenosyl cobalmin |
|
sources of cobalmin
|
- nature: synthesis by microorganisms in the animal intestine
- not present in vegetables - the only source of the vitamin are foods of animal origin eg liver kidney meats milk eggs, negligable amounts by intestinal flora neither plants nor animals can synthesize it |
|
function of vit b12
|
in food it occurs bound to a protein
to be utilized, it is first removed by acid hydrolysis in the stomach and then combines with the intrinsic factor which carries it to the ileum for absorption as the cobalmin intrinsic factor complex crosses the ileal mucosa, the intrinsic factor is released and the vitamin is transferred to the plasma the two coenzyme forms of cobalmin are methyl cobalmin in the cytoplasm and 5-deoxyadenosyl cobalmin in the mitochondria in man there are 2 biochemical reactions in which it participates: 1. methylation of homocysteine to methionine occurs in the cytoplasm and utilizes mehtyl cobalmin as coenzyme and N-methyl THF as methyl source 2. isomerization of l-methyl malonyl coA to succinyl coA by the enzyme L methyl malonyl coa mutase and the coenzyme 5 deoxy adenosyl cobalmin which occurs in the mitochondria |
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vitamin b12 deficiency manifestations
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1. PERNICIOUS ANAEMIA which is characterized by MACROCYTIC MEGALOBLASTIC ANAEMIA (due to the effect of b12 on folate metabolism)
2. NEUROLOGICAL DISORDERS due to the interference with myelin sheath integrity with sensory and motor losses (progressive demylelination of nervous tissue) 3. homocystinuria and methyl malonic aciduria |
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chemistry of vitamin c
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- gamma lactone of sugar acid
- strong reducing agent - contains enediol group from which removal of hydrogen produces dehydroascorbate. both forms are physiologically active and found in bodily fluids - oxalic acid is a catabolic product of ascorbic acid oxidation - can be synthesized from glucose (by uronic acid pathway) in all animals except humans and guinea pigs - it is easily destroyed by cooking. freezing has no deleterious effect upon this vitamin. |
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sources of vitamin c
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- fresh fruits eg orange, lemon, melon, berries
- leafy green vegetables and tomatoes |
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functions of vitamin c
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L ascorbic acid is the biologically active form, D ascorbic acid is not.
1. hydrogen carrier acting as a cofactor for certain enzymatic reactions 2. other nonenzymatic roles 3. antioxidant |
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enzymes that use vitamin c as a cofactor
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1. enzymatic hydroxylation of proline to hydroxy proline in collagen.
ie essential for maintaining the normal intercellular material of cartilage, dentine and bone for the integrity of capillary wall 2. tyrosine metabolism 3. hydroxylation reactions involved in the synthesis of some corticosteriods |
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vitamin c as nonenzymatic reducing agent
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1. aids in the absorption of iron by reducing it to the ferrous state in the stomach
2. enhances the utilization of folic acid by aiding the conversion of folate to tetrahydrofolate |
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vitamin c as an antioxidant
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biologically imp antioxidant, reducing the risk of cancer when present in adequate amounts in the diet
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manifestations of deficiency of vitamin c
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SCURVY
1. looseness of teeth, inflammation of gums (gingivitis) and bleeding from the gums 2. subcutaneous hemorrhage 3. anaemia (iron deficiency anaemia results from hemorrhage coupled with defects in both iron absorption and folate metabolism) 4. defect in bone formation 5. increased susceptibility to infections |