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141 Cards in this Set

  • Front
  • Back
where is haem synthesized
bone marrow (85%) and liver
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
what inhibits ALA synthesis
hematin and heme
PBG synthesis
2 ALA -----ALA DEHYDRATASE----> PBG + 2H2O
site of pbg synthesis
cytoplasm
what inhibits PBG synthesis
lead
uroporphyrinogen synthesis
4 porphobilinogen ---UROPORPHYRINOGEN I SYNTHASE ---> uroporphyrinogen I + 4 NH2

uroporphyrinogen I -----UROPORPHYRINOGEN III COSYNTHASE---> Uroporphyrinogen III
synthesis of coproporphyrinogen
uroporphyrinogen III ----DECARBOXYLASE----> coproporphyrinogen III + 4CO2
site of coproporphyrinogen synthesis
cytoplasm
protoporphyrinogen III synthesis
coproporphyrinogen III -----COPROPORPHYRINOGEN OXIDASE---> protoporphyrinogen III + 2CO2
site of protoporphyrinogen III synthesis
mitochondria
protoporphyrin IX synthesis
protoporphyrinogen III -----PROTOPORPHYRINOGEN OXIDASE---> protoporphyrin III + 6H

protoporphyrin III is protoporphyrin IX
heme synthesis
Protoporphyrin III ----HEAM SYNTHASE----> heam
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
how are RBCs broken down
reticuloendothelial system
haem catabolism
haem ---HAEM OXYGENASE[O2,NADPH]--> biliverdin + CO + Fe3+

biliverdin ---BILIVERDIN REDUCTASE---> bilirubin

[bilirubin + albumin] leave RES to enter liver.
where does heam catabolism take place
microsomal fraction of reticuloendothelial cells
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
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
cause of physiological jaundice in newborns
inability of neonatal liver to form bilirubin glucuronide at a rate comparable to that of bilirubal production
cause of congenital familial non-hemolytic jaundice
deficiency of UDP glucuronyl transferase enzyme --> accumulation of unconjugated bilirubin in the blood which is toxic to the brain and leads to mental retardation
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..
a) deficiency of metabolic products beyond the enzymatic block of Hb synthesis

b) accumulation of metabolites before the block
cause of acquired porphyrias
exposure to toxic compounds eg hexachlorobenzene and heavy metals eg lead

they inhibit ferrochelatase and ALA dehydratase.
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
characteristics of prehepatic jaundice
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
causes of prehepatic jaundice
1) RH incompatibility
2) chronic hemolytic anemia
3) mismatched blood transfusion
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
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
causes of hepatic jaundice
usually due to damage of hepatic cells due to

1. infections: hepatitis ABCD
2. toxic agents and chemicals eg CCL4, anesthetics
cause of post hepatic jaundice
obstruction of common bile duct (by stone or cancer in head of the pancreas)
characterizations of post hepatic jaundice
- 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
degradation of nucleoproteins
Nucleoproteins --> nucleic acids
by: proteolytic enzymes in the intestinal tract
degradation of nucleic acids
Nucleic acids --> mononucleotides
by: ribonucleases, deoxyribonucleases, polynucleotidases
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
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
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
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
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.
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
how do AMP and GMP regulate purine synthesis
AMP feedback regulates adenylosuccinate synthetase

GMP feedback inhibits IMP dehydrogenase
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
where does the salvage pathway occur
primarily in extrahepatic tissues
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)
second salvage mechanism for purines?
direct phosphorylation of purine ribonucleoside by ATP using kinase enzyme
what is the end product of purine catabolism
uric acid
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
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
vitamin b12 deficiency manifestations
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
chemistry of vitamin c
- 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.
sources of vitamin c
- fresh fruits eg orange, lemon, melon, berries

- leafy green vegetables and tomatoes
functions of vitamin c
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
enzymes that use vitamin c as a cofactor
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
vitamin c as nonenzymatic reducing agent
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
vitamin c as an antioxidant
biologically imp antioxidant, reducing the risk of cancer when present in adequate amounts in the diet
manifestations of deficiency of vitamin c
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