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Metabolism 76-81
Cederbaum (4 of 5)
85
Biochemistry
Graduate
08/11/2011

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Term
What is the active methyl donor?
Definition
S-Adenosylmethionine. Methionine+3ATP-->SAM+3Pi (via methionine adenosyl transferase)
Term
Basic steps of active methyl cycle?
Definition
Methionine-->SAM-->SAH-->Homocysteine-->Methione (last regeneration step by homocysteine methyl transferase, using B12 and CH3 from N5methylTHF)
Term
What pathways can homocyteine take and why would it choose either?
Definition
1)Regeneration to Methionine, 2)Transsulfuration pathway = Homocysteine+Serine-->Cysteine+NH3+aKB, does this if sufficient methionine in diet.
Term
What part of ATP adds to Methionine to make SAM?
Definition
Adenosine (ATP-->3Pi)
Term
Some critical biochemical rxns produced from methylation rxns?
Definition
Epinephrine, creatine, methylated nucleotides, phosphtidyl choline, melatonin.
Term
What is the fate of homocysteine's carbons after transsulfuration?
Definition
aKB-->Propionyl CoA-->Methylmalonyl CoA--> SuccCoA-->TCA cycle or OAA for gluconeogenesis.
Term
How does homocysteine contribute to cardiovascular disease?
Definition
Causes proliferation of smooth muscle cells that line arteries, also generates ROS which --> foam cells.
Term
Which co-factors are reqd to regenerate Methionine from Homocysteine?
Definition
B12 (cobalamine), N5-CH3-THF
Term
Co-factor reqd for transsulfuration pathway?
Definition
B6=PLP, req'd by both steps.
Term
Which are the 2 mammalian rxns requiring B12?
Definition
Homocysteine-->Methionine, PropionylCoA-->-->SuccCoA
Term
Why is cysteine such an important AA?
Definition
One of 3 that makes up GSH, reqd for protection against oxidative stress
Term
Potential causes of hyperhomocysteinemia?
Definition
In methyl cycle: 1)B12 deficiency, 2)def in enzyme that converts N5,N10methyleneTHF --> N5methylTHF, in transsulfuration pathway 3)mutated cysteine synthase or B6 def.
Term
Symptoms of elevated cysteine levels?
Definition
Neurological impairments/developmental probs, skeletal abnormalities, dislocation of lens, vomiting/GI irritability.
Term
How is hyperhomocysteinemia treated?
Definition
Depends on cause; 1)Supp w B12, B6, folate, enzymes, 2)Reduce Methionine intake - difficult bc essential so req's adding Cysteine as well.
Term
What is folic acid?
Definition
B-vitamin crucial for growth and development.
Term
What is THF?
Definition
Reduced (functional) form of folic acid.
Term
How are the one C fragments stored and where are they from?
Definition
Folate pool; mainly from serine, glycine, histidine.
Term
Which important biochemical does each form of carbon from folate pool play an important role in producing?
Definition
N5CH3THF - regeneration of Methioine from Homocysteine,
N5,N10CH2THF - synth of dTMP from dUMP,
N5,N10CHTHF - synth of purine rings
Term
How does folate def --> anemia & growth failure?
Definition
Reduced ability to synth dTMP --> reduced DNA replication and reduced purine synthesis.
Term
What causes Fetal Alcohol Syndrome?
Definition
1 reason is alcohol interferes w folic acid absorption.
Term
How do Sulfa drugs work?
Definition
Prevent synth of folic acid --> kills penicillin resistant bacteria but doesn't hurt us bc we don't synth folic acid.
Term
How is THF regenerated in the production of dTMP from dUMP?
Definition
2 Hs from THF (FH4) are used to reduce the carbon donated form dTMP to the methyl level leaving us w DHF. DHF+NADPH--->THF+NADP via DHF Reductase.
Term
How do anti-tumor drugs that inhibit folic biochem work?
Definition
Cancer cells need to make a lot of dTMP for DNA synth. Drugs can inhibit this in diff ways ie 1) Methotrexate inhibits DHF Reductase, 2) 5FU inhibits thymadilate synthase (dUMP+N5,N10CH2THF-->dTMP+DHF)
Term
How does folic acid biochem play a role in purine synth?
Definition
N5,N10methenylTHF (CH) make C2 & C8 of purine ring.
Term
How can histidine be used to test for THF def?
Definition
Histidine-->N-Formamino glutamate which + THF --> N5FormaminoTHF + glutamate. If inject lrg amounts of histidine and N5FormaminoTHF does not form = THF deficiency.
Term
How are the 3 oxidation stated of 1 C grps carried by THF related?
Definition
N5,N10-CH-THF reduced --> N5,N10-CH2-THF (or opp = methylene oxidized-->methenyl); N5,N10-CH2-THF reduced --> N5-CH3-THF.
Term
How are serine & glycine related?
Definition
Serine+THF<-->Glycine+N5N10-CH2-THF; Glycine+THF+NAD<-->N5N10-CH2-THF +CO2+NH3+NADH
Term
What co-factor is reqd to get Cs from serine & glycine into folate pool?
Definition
PLP=B6
Term
Structure of B12?
Definition
4 pyrrole units = corrin ring + ctr cobalt
Term
Co-factor forms of B12?
Definition
1)w Methyl --> Methyl Cobalamine, 2)w Deoxyadenosine --> Deoxyadenosyl Cobalamine
Term
Which cmpds are ultimately converted to SuccCoA, therefore requiring B12?
Definition
Threonine, Isoleucine, Methionine, Valine, odd-chain FAs.
Term
Fates of SuccCoA?
Definition
1)Enters TCA cycle, 2)Oxidized-->OAA-->gluconeogenesis
Term
What causes methylmalonyl aciduria?
Definition
1)Def of Methylmalonyl CoA Mutase, 2)B12 def , 3)Adenosyl Transferase def. All lead to inability to convert Methylmalonyl CoA-->SuccCoA either by a def of the enzyme, the enzyme's co-factor, or the enzyme that attaches deoxyadenosyl to B12.
Term
Symptoms of methymalonyluria?
Definition
Nausea, vomiting, convulsions, retardation, early death.
Term
Treatment of methylmalonyluria?
Definition
Synthetic protein diet that eliminates/limits the 4AAs that breakdown --> propionylCoA (threonine, isoleucine, methionine, valine), difficult bc all essential.
Term
What causes Pernicious Anemia?
Definition
Def of IF --> reduced B12 absorption --> folic acid accumulates as N5-CH3-THF due to inability to convert homocysteine+N5-CH3-THF--> methionine+THF; for some unknown reason body reacts as if def in N5-CH3-THF so all other forms of folic acid reduced to N5-CH3-THF --> no methylene for dUMP-->dTMP, no methenyl for purine synth --> RBCs cannot divide normally.
Term
How is Pernicious Anemia treated?
Definition
Cobalamine (B12) injection.
Term
Which 2 biochemical pathways req B12(cobalamine)?
Definition
1)Regeneration of Methionine from Homocysteine, 2)Methylmalonyl CoA-->SuccCoA (end of transsulfuration pathway)
Term
Fxns of nucleotides in biological systems (5).
Definition
1)Activated precursors of RNA/DNA, 2)Activated intermediates in biosyntheses (ie SAM methylation), 3)ATP as energy, 4)Component of NAD & FAD, 5)Metabolic regulators (ie AMP)
Term
Purine Bases incl:
Definition
Adenine, Guanine
Term
Pyrimidine bases incl:
Definition
Cytosine, Uracil, Thymadine.
Term
De Novo synth of purine bases:
Definition
R5P+ATP-->PRPP, PRPP+Glutamine+Glycine+Glutamine+Aspartate+N5,N10CHTHF-->IMP-->AMP or GMP.
Term
Nucleoside is:
Definition
Base + Ribose sugar.
Term
Nucleotide is:
Definition
Nucleoside + P
Term
What is the first purine to be synth by the de novo pathway?
Definition
Inosine, has hypoxanthine base.
Term
Role of folate in purine synth?
Definition
C2 & C8
Term
Where does ribose sugar come from?
Definition
G6P-->PPP-->R5P
Term
What directs whether IMP will be converted to GMP or AMP?
Definition
Both inhibit their own synthesis, AMP reqs GTP, GMP reqs ATP.
Term
Rate limiting step of purine synth and how is it regulated?
Definition
PRPP+Glutamine-->5-phosphoribosyl-1-amine via amido phosphoribosyltransferase. Inhib by IMP, AMP, GMP (products).
Term
What happens to the bases when RNA is broken down?
Definition
1)Excreted as uric acid or 2)Returned to purine nucleotide pool via purine salvage pathway.
Term
Basic mech of purine salvage pathway?
Definition
Rather than being excreted as uric acid, purine base is attached to PRPP --> ribonucleotide.
Term
What results from a def of hypoxanthine-guanine phosphoribosltransferase?
Definition
Lesch-Nyhan syndrome -->compulsive self-destruction, elevated PRPP, incr in de novo purine synth, overproduction of urate from purine base breakdown-->kidney stones/gout.
Term
What causes gout?
Definition
High meat diets, excess alcohol, kidney disease, Lesch-Nyhan --> high lvls of uric acid in blood --> reacts w metals --> urate forms insoluble crystals which deposit in joints -->attacked by immune system.
Term
How is gout treated?
Definition
1)Allopuranol - inhibits xanthine oxidase so purines only breakdown to hypoxanthine/xanthine which are more soluble and easier to excrete, 2)Methotrexate/Colchicine block immune system & inflammatory rxns.
Term
How does purine breakdown play a role in ischemia reperfusion injury?
Definition
The breakdown of ATP (via this pathway)-->xanthine, xanthine oxidase creates free radical (H2O2).
Term
Where would you find CPSI vs CPSII? Why is this important?
Definition
CPSI in liver mito (urea cycle), CPSII in all cell cyto (catalyzes 1st step of pyrimidine biosynth). Keeps pathways separated.
Term
Fxn of Ribonucleotide Reductase?
Definition
Reduce ribonucleotides to deoxyribonucleotides.
Term
Rate limiting step of pyrimidine biosynth? How is it regulated?
Definition
CarbamoylP+Aspartate-->N'carbamoyl Aspartate + Pi via Carbamoyl Aspartate Transcarbamylase. Inhib by pyrimidines, stim by ATP (a purine).
Term
How is CPSII regulated?
Definition
Inbib by UMP (product), stim by PRPP.
Term
How are the urea cycle and pyrimidine synth interrelated?
Definition
Orotic acid; OTC def-->CarbamoylP accumulation-->orotic acid or can leave mito and join pyrimidine synth --> UMP.
Term
Oxidation/Reduction steps of Ribonucleotide Reductase?
Definition
Uses NADPH to reduce ribose-->deoxyribose; thioredoxin reduces reductase disulfide back to sufhydryl state using FADH2; NADPH reduces FAD back to FADH2.
Term
What are the 3 "sites" on RR?
Definition
1)Overall activity site, 2)Substrate specificity site, 3)Catalytic site.
Term
What does catalytic site of RR contain?
Definition
1)Essential sulfhydryl grps, 2)Iron-Oxygen complex (powerful oxidant!), 3)Tyrosine residues.
Term
How can RR be targeted to fight cancer?
Definition
Hydroxyurea quenches tyrosine free radical --> cells no longer divide.
Term
How do tyrosines on RR extract Hs from ribonucleotides?
Definition
Via generation of a free radical.
Term
How does RR substrate specificity site work?
Definition
ATP (a purine) binds activity site --> forms deoxypyrimidines (dCDP, dUDP) --> either dCDP or dTTP displaces ATP --> signifies enough pyrimidines so switches to producing purines --> dGTP displaces dTTP --> makes other purine (dATP) --> dATP displacing dGTP turns system off.
Term
What causes SCIDS?
Definition
Deficiency in adenosine deaminase (which catalyzes AMP-->hypoxanthine in purine uric acid pathway), if adenosine isnt getting broken down neither is deoxyadenosine (dATP) so RR is constituitively turned off --> no WBC division --> no Abs.
Term
Glucogenic and Ketogenic metabolites produced by AA catabolism.
Definition
Glucogenic: Pyruvate, aKG, SuccCoA, Fumarate, OAA.
Ketogenic: Acetoacetate, AcCoA.
Term
Which tissues breakdown AAs and why?
Definition
All tissues, esp liver & muscle. AAs can't be stored.
Term
Which is the only purely ketogenic AA?
Definition
Leucine
Term
Which AAs break down to pyruvate?
Definition
Tryptophan, Alanine, Glycine, Serine, Cysteine.
Term
AAs that break down to aKG?
Definition
Glutamine, Glutamate, Histidine, Proline, Arginine.
Term
AAs that break down to SuccCoA?
Definition
Methionine, Threonine, Isoleucine, Valine.
Term
AAs that break down to OAA?
Definition
Asparagine, Aspartate.
Term
AAs that break down to fumarate?
Definition
Phenylalanine, Tyrosine.
Term
Which AA do sulfates come from and what are they used for?
Definition
Cysteine; Remove toxins from body, steroids circulate as ester-sulfates, component of joint glycoproteins.
Term
Which are the branch chain AAs and how are they broken down?
Definition
Leucine, valine, isoleucine. Transamination --> aKetoAcid of AA --> CoA derivative (by aKetoAcid DH) -->other CoAs (by acyl CoA DH).
Term
Deficiency of aKetoAcid (branched chain) dehydrogenase causes what?
Definition
MSUD; build up of branched-chain AAs & aKetoAcids; very toxic to nervous system --> failure to thrive, coma, death before age 2 if untreated.
Term
How is MSUD treated?
Definition
Synthetic protein diet restricting branch-chain AAs.
Term
What does phenylalanine break down to and what is the necessary co-factor?
Definition
Phenylalanine-->Tyrosine-->Fumarate+AcetoAcetate; THB (tetrahydrobiopterin), donates Hs (similar to THF), regenerated DHB-->THB via DHB reductase+NADH.
Term
What does a def in phenylalanine hydroxylase cause and how is it treated?
Definition
Phenylketonuria (PKU); built up phenylalanine enters side pathways --> phenylpyruvate & phenylacetate (phenylketones) --> severe neurological disturbances. Treat by restricting phenylalanine + supplementing w tyrosine.
Term
What besides a def in phenylalanine hydroxylase can cause PKU and how is it treated?
Definition
THB def, supplement. DHB reductase def, v difficult to treat.
Term
What causes black urine?
Definition
Alkaptonuria= def of homogentisic acid oxidase (tyr-->homogentisate-->fumarate); also req a lot of Vit C; assoc w severe arthritis.
Term
Which AAs are both ketogenic and glucogenic?
Definition
Phenylalanine, tyrosine.
Term
What co-factor is reqd as a reducing agent for aromatic AA hydroxylation?
Definition
THB=tetrahydrobiopterin
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