Ch 40 Flashcards
What can CO2 be transferred by
biotin
Carbon in lower levels of oxidation than CO2 can be transferred by
tetrahydrofolate (FH4) aka vit B12 and S-adenosylmethionine (SAM)
what is FH4 produced from
vitamin folate
what is the primary 1-carbon carrier in the body
FH4
where does FH4 obtain 1-carbon units
serine, glycine, histidine, formaldehyde, and formate
how can folate exist in several different forms
the 1-carbon unit can be oxidized or reduced
can a carbon reduced to methyl-FH4 be reoxidized
no
what is the term ‘folate’ used for
water-soluble B-complex vitamin that fxns in transferring single-carbon groups at various stages of oxidation
examples of uses of 1-carbon group pool
dUMP to dTMP, glycine to serine, precursers of purine bases, and vit B12
What 2 rxns is vit B12 involved in
1) rearrangement of methyl group of L-methylmalonyl CoA to form succinyl CoA 2) transfers methyl group from FH4 to homocysteine forming methionine
What is SAM produced from
methionine and ATP
fxn of SAM
transfers methyl group to precursors that form many cmpds like creatine, phosphatidylcholine, epinephrine, melatonin, methylated nucleotides, and methylated DNA
only rxn in which methyl-FH4 can donate the methyl group
creation of methionine from homocysteine
what occurs id vit B12 or FH4 levels are insufficient
homocysteine will accumulate
methyl trap hypothesis
occurs when vit B12 deficient, methyl unable to leave FH4; folate deficient even though normal amounts present
what does a folate deficiency lead to
megaloblastic anemia due to inability of blood cell precursors to synthesize DNA
schilling test
ingest radioactive Co60 crystallie vit B12 and 24 hour urine smpl collected; determine amount of B12 absorbed
5-fluorouracil as chemotherapy agent
pyrimidine analong which is converted in cells to FdUMP that causes thyminless death and prevent tumor growthl prevents dUMP to dTMP
what does elevation in methylmalonic acid indicate
suspect vit B12 deficiency
why are folate deficiencies common in chronic alcoholics
inadequate dietary intake, damage to intestines and brush border enzymes, defect in enterohepatic circulation, liver damage, kidney reabsorption
ineffective erythropoiesis
increased marrow cellularity, but decreased red cell production
coemnzyme that fxns in accepting 1-carbon groups
tetrahydrofolate polyglutamate aka FH4
3 main structural components of FH4
1) bicyclic pteridine ring 2) para-aminobenzoic acid 3) polyglutamate tail consisting of several glutamate residues joined in amide linkage
where is 1-carbon unit accepted/bound in FH4
N5 or N10 or both
what does folic acid/folate refer to
most oxidized form of pteridine ring of FH4
what reduces folate to dihydrofolate to tertrahydrofolate
dihydrofolate reductase in cells; reduction is favored direction of rxn
how do sulfa drugs work against some bacterial infections
analogs of para-aminobenzoic acid and interfer with synthesis of folate
US recommended dietary allowance of folate
400 ug for adult men and women
good sources of folate
green leafy vegies, liver, yeast, legumes, some fruits
what form is the dietary folate from natural sources
reduced coenzyme form
how is folate absorbed
folate conjugases in lumen cleave off glutamate residues producing monoglumate form of folate which is absorbed
what happens to absorbed folate in intestinal cells
converted to N5-methyl-FH4 which enters portal vein and goes to liver
how does N5-methyl-FH4 travel in blood
loosely bound to albumin and other plasma proteins
how can folate deficiency be tested
histidine load test; if folate deficient, then FIGLU appears in urine in excess amounts
major carbon source of one-carbon groups in human
serine; hydroxylmethyl group transferred to FH4 via hydroxymethyltransferase
how is FIGLU (formiminoglutamate) produced
degradation of histidine
why does folate deficiency cause DNA synthesis issues
required in purine base systhesis at carbons 2 and 8; also hindered due to dTMP synthesis
how does the corrin ring in vit B12 differ from heme
2 of the 4 pyrrole rings are directly joined rather than by a methylene bridge
what is within the ring of vit B12 (aka cobalamin)
Cobalt; can for a bond with a ccarbon atom
what form is B12 in supplements
cyanobalamin in which a CN group is linked to the cobalt
what does methotrexate resemble
folate except an amino group on C4 and methyl on N10
what is methotrexate used for
anticancer drug; inhibit dihydrofolate reductase and prevent conversion of FH2 to FH4
major source of vit B12
dietary meat, eggs, dairy products, fish, poultry, and seafood
2 forms of ingested vit B12
free or bound to dietary proteins
what does free B12 bind
proteins known as R-binders (aka haptocorrins or transcobalamin I)
where are R-binders produced
salivary glands and gastric mucosa
what occurs to haptocorrins in the small intestine
pancreatic enzymes digest them and release B12 which then binds to intrinsic factor
what is intrinsic factor
a glycoprotein secreted by parietal cells in stomach
where does the intrinsic factor-vit B12 complex attach
specific receptors in ileum
Besides pernicous anemia, what other malfunctions can cause vit B12 deficiency
pancreatic insufficiency or high intestinal pH (too little stomach acid); both prevent degradation of R-binder-B12 complex, so B12 can’t bind intrinsic factor
what rxns is S-adenosylmethionine (SAM) used in
add methyl groups to either O or N; more than 35 rxns require
What does folate add 1-carbon groups to
carbon or sulfur
examples of SAM use
guanidinoacetate to creatine, norepinephire to ephinephrine, acetylserotonin to melatonin, and nucleotides to methylated nucleotides; inactivation of catecholamines and serotonin
what does SAM form when it donates its methyl group
S-adenosylhomocysteine which is hydrolyzed to form homocysteine and adenosine
2 major clinical manifestations of vit B12 deficiency
1) hematopoietic due to folate metabolism 2) neurologic due to hypomethylation in nervous system
classical clinical presentation of neurologic issues in B12 deficiency
numbness and tingling of hands and feet, diminished vibratory and position sense, progression to spastic gait disturbance
what are neurologica symptoms in vit B12 deficiency caused from
hypomethylation due to inability to recycle homocysteine to methionine and from there to SAM
what is required for the synthesis of SAM
methionine-either obtained from diet or through homocysteine
how do methyl groups get trapped in N5-methyl-FH4
vit B12 deficiency or methionine synthase enzyme defect
how is homocysteine synthesized
S-adenosylhomocysteine (which is hydrolyzed to form homocysteine and adenosine)
2 fates of homocysteine
remethylated to methionine or condensed with serine to form cystathionine
2 routes to methionine production
N5-methyl FH4 requiring B12 or betaine donates a methyl group to homocysteine in liver
what does homocysteine to cystathionine require
PLP
What occurs with homocysteine if vit B12 not available
breaks down to form cystathionine which forms cysteine, which is has neg feedback causing accumulation of homocysteine
what occurs wih enzyme defect in N5, N10-methylene-FH4 to N5-methyl-FH4
N5-methyl-FH4 too low to convert homocysteine to methionine, causing homocystine elevation
what occurs when cystathionine B-synthase defect occurs or vit B 6 deficiency
homocysteine level elvated since conversion to methionine can’t accomidate all the homocystine accumulated
what is choline oxidized to form
betaine aldehyde, which is oxidized to betaine (trimethylglycine); an alternative route for methionine producation in liver
how does folate deficiency reduce DNA synthesis
decreased availability of deoxythymidine and purine nucleotides
