CH 39 Flashcards
what is the quintessential coenzyme of aa metabolism
pyridoxal phosphat (derived from vit B6)
what is pyridoxal phosphate involved in in aa degradation and synthesis
removal of amino groups through transamination rxns and donation of amino groups
what else is pyridoxal phosphate involved in
rxns that involve carbon skeleton of aas
what coenzyme is used to transfer one-carbon groups at various oxidation states
Tetrahyrdofolate (FH4)
what aas does FH4 help degrade
serine and histidine
what aas does FH4 help synthesize
glycine
what is the cofactor required for ring hydroxylation rxns…in what aas
Tetrahydrobiopterin (BH4); phenylalanine to tyrosine
how many of the 20 common aas can be synthesized in the body
11-most are aas used for synthesis of additional nitrogen-containing cmpds
what is glycine used as a substate for
porphyrin and purine synthesis
what is glutamate used as a substrate for
neurotransmitter and purine synthesis
What is aspartate used a substrate for
purine and pyrimidine synthesis
what can 9 of the 11 nonessential aas be synthesized from
glucose plus a source of nitrogen (like another aa or ammonia)
what do 2 of the 11 nonessential aas require for synthesis and what are they
tyrosine and cysteine require another nonessential aa for synthesis (phenylalanine and methionone respectively)
what 4 aas are produced from glucose via glycolytic pathways components
serine, glycine, cysteine, and alanine
what provides components for other 6 glucose dependent nonessential aas
TCA cycle intermediates
what is alpha-Ketoglutarate the precursor for
glutamate, glutamine, proline, and arginine
what is oxaloacetate the precursor for
aspartate and asparagine
what can almost every aa be degraded to when used as a fuel source
NADH, an electron source for oxidative phosphorylation
what occurs in the liver during fasting
aa carbon skeletons produce glucose, ketone bodies, and CO2
what occurs in liver during fed state
convert intermediates of aa metabolism to glycogen and triacylglycerols
when are aas considered glucogenic
if carbon skeletons can be converted to precursor of glucose
when are aas considered ketogenic
if carbon skeletons can be converted directly to acetyl CoA or acetoacetate
what do aas synthesized from glycilysis intermediates produce when degraded
pyruvate
what occurs to aas synthesized by TCA cycle intermediates when degraded
reconverted back to the same intermediates
how is histidine degraded
converted to glutamate then to TCA intermediate alpha-ketoglutarate
what do methionine, threonone, valine, and isoleucine form when degraded
succinyl CoA
What do phenylalanine (thus tyrosine as well) form when degraded
fumarate
glucogenic and ketogenic aas that form glucose plus acetyl CoA
tryptophan, isoleucine, threonine
glucogenic and ketogenic aas that form glucose plus acetoacetate
phenylalanine and tyrosine
what two essential aas are only ketogenic
lysine and leucine (only produce acetoacetate and acetyl-CoA)
guthrie bacterial inhibition assay
spores of Bacillus subtilis plated with B2-thienylalanine (inhibitor of growth); blood sample placed in plate…if phenylalanine >2-4 mg/dL bacterial growth will occur
3 important cofactors in aa metabolism
pyridoxal phosphate, tetrahydrofolate (FH4), tetrehydrobiopterin (BH4)
what is serine synthesized from
3-phosphoglycerate; serine goes on to produce glycine and cysteine
what is alanine synthesized from
transamination of pyruvate
Step 1 of serine synthesis from glucose
3-phosphoglycerate is oxidized to a 2-keto cmpd (3-phosphohydroxypyruvate)
Step 2 of serine synthesis from glucose
3-phosphohydroxypyruvate is tranaminated to form phosphoserine
Step 3 in serine synthesis from glucose
phosphoserine phosphatase removes the phosphate fomring serine
where are the major sites of synthesis for serine
liver and kidney
what is serine generally degraded to by transamination
hydroxypyruvate, followed by reduction and phosphorylation to form 2-phosphoglycerate (intermediate of glycolysis)
what can glycine be synthesized from
serine, minorly threonine
medically importantt conversion of glycine
to glyoxylate by enzyme D-amino acid oxidase
what can occur to glyoxylate once formed
oxidized to oxalate, which is sparingly soluble and tend to precipitate in kidneys
what precent of axalate formation in liver comes from glycine metabolism
40.00%
primary oxaluria type 1 (PH 1)
lack of transaminase that can convert glyoxylate to glycine; causes renal failure
what does glycine cleavage enzyme create from glycine
CO2, ammonia, and a carbon that is donated to FH4
cysteine synthesis
carbons and nitrogen from serine and sulfur from methionine
Step 1 of cysteine synthesis
serine reacts with homocysteine (produced from methionine) to form cystathionine
what is step 1 of cysteine synthesis catalyzed by
Beta-synthase
Step 2 of cysteine sythesis
cleavage of cystathionine via cystathionase produces cysteine and alpha-ketobutyrate
what does alpha-ketobutyrate break down into
succinyl CoA via propionyl CoA
What do cystathionine B-synthase and cystathionase require
pyridoxal phosphate (PLP)
how does cysteine regulate its own production
inhibits cystathionine B-synthase; helps adjust form dietary cysteine
when does cysteine become an essential aa
when methionine supply inadequate; excess dietary custeine ‘spares’ methionine
what is cysteine degraded into
notrogen converted to urea, carbons to pyruvate, sulfur to sulfate
what are the 2 fates of sulfate
in aqueous soln, basically makes sulfuric acid; used to generate PAPS
What is PAPS
3’-phosphoadenosine 5’-phosphosulfate; used as a sulfate donor in modifying carbs or aas in various structures (like GAGs)
major degrative route of methionine, homocystein, and cysteine
methionine to homocysteine to cysteine; only route for homocysteine degradation
what occurs if there is a vit B6 deficiency or congenital cystathionine B-synthase deficiency
homocystinemia since homocysteine only has one degradative route; associated with Cardiovascular disease
what is the medical effect of cystathiouria
benign disorder; common in remature infants
cystinuria
defect in transport protein of intestinal epithelial cells; allows resorption of aas affected by renal cells, but cysteine in not very soluble and forms renal caniculi aka stones
cystinosis
defective carrier that normally transports cysteine across lysosomal membrane; forms crystals causing renal failure by6-12 years old
how is alanine produced
from pyruvate via transamination rxn catalyzed by alanine aminotransferase (ALT); reversible rxn
why is alanone the major gluconeogenic aa
produced in many tissue to transport nitrogen to liver
how is glutamate formed
alpha-ketoglutarate via transamination or glutamate dehydrogenase rxn; both reversible
how can glutamete form glucose in liver
alpha-ketoglutarate forms malate, which produces glucose via gluconeogenesis
glutamate is made in synthesizing what other aas
glutamine, proline, ornithine, and arginine
what other important molecules does glutamate produce
glutamyl moiety of glutathione; an important antioxidant
glutamine formation
from glutamate by glutamine synthetase-ads NH4+ to carboxyl group of the side chain forming an amide
what 3 human enzymes can fix free ammonia
glutamine synthase, glutamate dehydrogenase, and carbamoyl phosphate synthetase I
what is glutamine reconverted to glutamate by
glutaminase; important in kidneys-ammonia produced wnters urine and can be used to excrete metabolic aids
what is the relationship btwn homocysteine and homocystine
homocystine is 2 homocysteines with a di-sulfide bond
proline synthesis step 1
glutamate phosphorylated
proline synthesis step 2
converted to glutamate 5-semialdehyde by reduction of the side-chain carboxyl group to an aldehyde
proline synthesis step 3
semialdhyde spontaneously cyclizes
proline synthesis step 4
cyclic cmpd reduced to form proline
when is hydroxyproline formed
when proline is incorporated into collagen by prolyl hydroxylase system
proline degradation
converted back to glutamate semialdehyde, which is oxudized to form glutamate; used different ezymes than synthesis
hydroxyproline degradation
completely different than proline; aldolase-like rxn occurs once ring hydrolyzed
arginine synthesis
glutamate via glutamate semialdehyde transamination to form ornithine
what is ornithine
intermediate of urea cycle
where is ornithine aminotransferase activity the greatest
small intestine; rxns of urea cycle produce arginine
when is arginine an essential aa
during periods of growth when urea cycle argenine synthesis is not sufficient
what occurs when arginine is used for protein synthesis
levels of ornithine drops and stimulates formation from glutamate
how is arginine degraded
arginase cleaves to form urea and ornithine
what occurs when ornithineis present in excess for urea cycle requirements
tansaminated to glutamate semialdehyde and reduced to glutamate; requires PLP
histidine formation
is an essential aa
histimine degradation
5 of carbons form glutamate
aspartate producation
transamination of oxaloacetate; readily reversible
aparagine formation
from aspartate in rxn where glutamine provides nitrogen for amide
asparaginase fxn
hydrolyzes asparagine to NH4+ and aspartate
major route for asparatate degradation
oxaloacetate; although carbons can form furmarate in urea cycle
process of minor route of asparatae degradation
reacts with inosine monophosphate (IMP) to form adenylosuccinate intermediate which is cleaved to form AMP and fumarate
phenylalanine degradation
converted to tyrosine by hydroxylation rxn; tyrosine is oxidized and forms acetoacetate and fumartate
These amino acids degrade to form what: methionine, valine, isoleucone, and threonine
propionyl CoA then succinyl CoA
where else is propionyl CoA produced
oxidation of odd-chain fatty acids
Leukemic cells and many tumor cells require what aa for their growth
asparagine; asparaginase has been used as anti-tumor agent
what occurs to propionyl CoA once formed
carboxylated and forms D-methylmalonyl CoA (requires biotin); this is racemized to L-methylmalonyl CoA
what does the reation leading to succinyl CoA from propionyl CoA require
vit B12
methionine degradation
converted to S-adenosylmethionine (SAM) which donates its methyl to other cmpds to form D-adenosylhomocysteine (SAH)
What happens to SAH
converted to homocysteine
how can methionine be regenerated
FH4 plus homocysteine plus B12
what are carbons of homocysteine metabolized to
alpha-ketobutyrate, which undergoes oxidative decarboxylation to propionyl CoA
homocystinuria is caused by…
enzyme cytathionase B-synthase and cystathionase deficiencies as well as methyltetrahydrofolate (Ch3-FH4) or methyl-B12
how can you get deficiencies in Ch3-FH4 or methyl-B12
inadequate dietary intake or defective enzymes that join methyl groups to FH4
threonine degradation
PLP-requiring dehydratase to ammonia and alpha-ketobutyrate
Which aa are universal fuels
valine, isoleucine, and leucine; all are branched-chain aas
what carries out branched chain aa oxidation
mitochondria of most tissues; muscle has highest level
what aa content in a protein consist of branched-chain aas
25.00%
two fxns of valine and isoleucine degradation
fuel and provide intermediates for TCA
first step in branched chain aa degradation
transamination; remaining steps analagous to B-oxidation of fatty acids-NADH and FAD2H generated
what do valine and isoleucine convert to when degraded
succinyl CoA; isoleucine also forms acetyl CoA
What does leucine form when degraded
acetoacetate and acetyl CoA-strongly ketogenic
what is wrong in maple syrup urine disease
branch-chain alpha-keto acid dehydrogenaase is defective; leads to neuro complications
what is difficult in treating maple syrup urine disease
involves 3 amino-acids, so difficult to use dietary constrictions
alcaptonuria
homogentisate can’t be further oxidized since homogenitsate defective (intermediate in tyrosine metabolism)
what converts phenylalanine to tyrosine
hydrolated by phenylalanine hydroxylase (PAH)-requires O2 and tetrahydrobiopterin
what is tetrahydrobiopterin converted to in the rxn
quininoid dihydrobiopterin, which must be reconverted in order for rxm to continue producing tyrosine
tryptophan is oxidized to form…
alanine, formate, and acetyl CoA
what can be produced from the ring stucture of tryptophan sparing niacin
NAD and NADP
what conditions can cause tyrosinemia
prematurity, enzyme defects
tyrosinemia II
defect in tyrosine aminotransferase (TAT) and may lead to lesion of eye and skin as well as neuro problems
Tyrosinemia I (aka tyrosinosis)
defect in fumarylace-toacetate hydrolase; acute form associated with liver failure, cabbagelike body odor, and death within 1st year
diseases caused by deficiencies in phenylalanine-tyrosine conversion
PKU, tyrosenemia, alcaptonuria
what occurs with defect in dihydropteridine reductase (DHPR-required for BH4 regeneration)
hyperphenylalaninemia which responds to diet change, but symptoms persist and patients die within first 2 years
what is BH4
a cofactor of PAH
what occurs with BH4 defect
diet control lowers phenylalanine, but BH4 is required for synthesis of neurotransmitters
what neurotransmitter is BH4 required for
tryptophan to 5-hydroxytryptophan and tyrosine to L-dopa
when does pellagra occur
insufficiency of niacin and tryptophan
What does pellagra cause
dermatitis, diarrhea, dementia, finally death
what occurs in tryptophan degradation if vit B6 is deficient
enters minor pathway creating xanthurenic acid
lysine degradation
can’t be directly transaminated at either of its amino groups and is degraded by a complex pathway
intermediates of lysine degradation
saccharopine, alpha-ketoadipate, crotonyl CoA; NADH and FADH2 generated in process; ultimately produces acetyl CoA-strictly ketogenic
indidence of PKU
100 per million births with wide geographic/ethnic variation
cause of PKU
defective PAH gene
what causes symptoms of PKU
competative interaction of phenylalanine with brain aa transport systems and inhibition of neurotransmitter synthesis; lead to impaired myelin synthesis and delayed neuro development
what accumulates in cystathionine B-synthase deficiency
homocysteine and methionine in the blood
what pathological effect of the eyes occur in cystathionine B-synthase deficiency
zzonular fibers that normally hold the lens of the ye become frayed and break causing dislocation of the lens
what pathological effect of the bones occur in cystathionine B-synthase deficiency
skeleton has loss of ground substance (may explain curvature of spine often seen); long bones are also elongated leading to tall stature
what do animal experiements of increased homocysteine and methionine in the brain reveal
may trap S-adenosylhomocysteine diminishing adenosine levels; adenosine normally acts as a CNS depressant
why may methionine not appear in urine despite elevated levels
renal tubular reabsoption of methionine is highly efficient
why is homocysteine found in urine when elevated
less efficiently reabsorbed and excess of 1 mmol/day may be excreted
type II homocystinuria
defect in synthesis of methyl cobalamin; required for methylation of homocysteine to form methionine
type III homocystinuria
defect in synthesis of N5-methyltetrahydrofolate; required for methylation of homocysteine to form methionine
type I homocystinuria
cystathionine B-synthase deficiency; homocysteine and methionine levels elevated
what is associated with elevated homocysteine levels, but there is no known mechanism
increased thrombi and emboli
what therapies are in place for homocystinurias
diet control of homocysteine and methionine; high oral doses of pyridoxine (vit B6)-50% of type 1 respond to
