biochem exam 5 Flashcards
what are the three classes of genetic disorders that affect metabolic pathways?
lysosomal storage, toxin-generating, and energy production
what is lysosomal storage disorder?
caused by deficiencies in lysosomal enzymes or function –> substrates will accumulate over time, leading to swollen lysosomes and impaired cell structure and function
most LSDs present after 2-3 months of age and involve PROGRESSIVE DEGENERATION of neurologic function and skeletal deformities –> enzyme replacement therapy is used as treatment
ex: I-cell disease, Pompe disease, Gaucher, Tay-Sachs, Niemann-Pick
what is toxin-generating disorder?
result in accumulation of toxic substances –> treatment = avoiding unnecessary activation of affected pathway and/or inactivating or eliminating toxin
ex:
neurotoxin-generating: urea cycle defects, phenylketouria, maple syrup disease, organic acidurias, Refsum disease
other toxin-generating: G6PDH deficiency, hereditary fructose intolerance, galactosemia, dyslipidemias, primary oxaluria, homocystinuria
what is energy production disorder?
results in FASTING hypoglycermia, few are limited to muscle metabolism and result in muscle weakness with little or no association with faster metabolism (very FEW affect both fed and fasting metabolism, like pyruvate kinase deficiency in erythrocytes)
treatment = avoiding precipitating events (fasting, illness, exercise), ACUTE decompensation is treated by administration of IV glucose (to go back to fed state), some disorders of fasting metabolism become less severe as one reaches adulthood
ex: glycogen storage disorders (EXCEPT Pompe disease), defects in gluconeogenesis, MCAD deficiency
what are the 4-carbon non-essential AAs?
asparagine and aspartate (differ by one amide group)
OAA –> asp –> asn
what are the 2 or 3 carbon non-essential AAs?
glycine, serine, cysteine, and alanine
glucose –> 3-phosphoglycerate –> serine <–> glycine and serine –> cysteine, 3-phosphoglycerate –> 2-phosphoglycerate –> pyruvate <–> alanine
what are the 5 carbon non-essential AAs?
glutamine, glutamate, proline, and argnine
citrate –> isocitrate – alpha-KG <–> glutamate –> glutamine or glutamate –> glutamate semialdehyde –> proline and arginine
what do glucogenic AAs produce?
pyruvate or TCA intermediates
use for gluconeogenesis
what do ketogenic AAs produce?
acetyl CoA
what AAs are ONLY ketogenic?
lysine and leucine
some AA may appear in both groups like tyrosine
how are the 2-3 carbon non-essential AAs degraded?
glucose <–> 3-phosphoglycerate which can convert to serine <–> glyine, serine –> 2-phosphoglycerate, or serine –> cysteine
2-phosphoglycerate + cysteine –> pyruvate <–> alanine
how is ser made and degraded?
from 3-PG and degraded to 2-PG
synthesis
begins with OXIDIZING alcohol side chain of 3-PG to ketone making alpha-keto acid –> TRANSAMINATION making alpha-AA –> HYDROLYSIS of phosphate –> SERINE
degrade
SERINE –> TRANSAMINATION –> REDUCTION –> PHOSPHORYLATE –> 2-PG –> glycolysis
how is gly made?
it is interconverted with ser by SERINE HYDROXYMETHYLTRANSFERASE and can also be degraded by glyoxylate pathyway or glycine cleavage enzyme
serine <–> glycine via serine hydroxymethyltransferase, glycine –> CO2, NH4+, and methyl attached to tetrahydro-folate via glycine cleavage enzyme OR transaminase and D-AA oxidase –> glyoxylate –> oxalate
both serine hydroxymethyltransferase and glycine cleavage enzyme use FH4 as a cofactor
what are serine hydroxymethyltransferase and glycine cleavage enzyme important?
these reactions are important because they provide carbons for the cofactor tetrahydro-folate (B9)
why is the oxalate produced from glycine important?
it can precipitate with calcium and form kidney stones
about 40% of oxalate production in the body is via this reaction
what happens when there’s a deficiency in the pyruvate-alanine aminotransferase in the glycine pathway?
can lead to PRIMARY OXALURIA type I because transaminase is not converting glycoxylate back to glycine, instead glycoxylate will build up and form oxalate = kidney stones
what is calcium oxalate?
a strong irritant, contain need-like crystals that cause pain and edema after coming into contact with lips, tongue, oral mucosa, conjunctiva, or skin –> lasts up to 2 weeks
how is cys made?
made from serine with sulfur coming from methionine in form of homocysteine
what can a deficiency in cystathinone beta-synthase cause? what are the symptoms?
type 1 homocystinuria
patients will experience PREMATURE VASCULAR DISEASE with 25% dying from thrombic complications
signs = subluxation (dislocation) of lenses in eyes, mental retardation, and osteroporosis in childhood
how is cys degraded?
catabolized to pyruvate and sulfate, also route for catabolism of met
- sulfyhydryl group oxidized to sulfinic acid then transamination with alpha-KG produces pyruvate, glutamate, and sulfite
- sulfite oxidized to sulfate which can be incorporated into PAPS or excreted in urine
serine + homocysteine –> cystathinone via beta-cystathionine synthetase using PLP as cofactor –> cystathionine –> cysteine + alpha-ketobutyrate via cystathionase using PLP as cofactor –> cysteine sulfinic acid (this step produces glutamate, pyruvate, and uses PLP) –> sulfite –> sulfate –> PAPS or urine
note: alpha-ketobutyrate can be converted to propionyl CoA –> methymalonyl CoA –> succinyl CoA
how is alanine made?
alanine aminotransferase of amino group from glutamate to pyruvate –> alanine and alpha-KG
how are glu, gln, pro, and arg made?
they’re all made from and degraded to alpha-KG
what is the significance of his?
it is also degraded to alpha-KG, but CANNOT be synthesized by the body so it is an ESSENTIAL aa
HOWEVER, it is not rapidly degraded, so dietary requirements are low because it can be efficiently recycled
how is glu and gln made?
glu is made from and converted to alpha-KG, gln is made from and converted to glu
glu <–> alpha-KG via GDH and aminotransferases
glu <–> gln via glutamine synthetase and glutaminase
how is pro and arg made?
glutamate semialdehyde is an intermediate in synthesis and degradation of pro and arg
side chain of glut can be reduced to aldehyde –> glu semialdehyde –> semialdehyde SPONTANEOUSLY CYCLIZE and be reduced to pro or ornithine via ornithine aminotransferase
via urea cycle, ornithine can be converted arg (undergo whole urea cycle to generate arg)
all processes are REVERSIBLE
how is asp and asn made?
asp and asn are converted and made from OAA
OAA <–> asp via transamination using PLP
asp <–> asn via asparagine synthetase or reversed using asparaginase
asp –> asn uses N group from glutamine for transamination
this reaction is analogous to alpha-KG, glu, gln reaction
how is fumarate formed?
asp, phe, and tyr generate fumarate during their catabolism
recall: fumarate can be generated in urea cycle from asp
phe and tyr are both degraded to fumarate and acetoacetate
how is succinyl CoA formed?
met, thr, ile, and val are all degraded to succinyl CoA via propinyl CoA
recall: propionyl CoA is also made in oxidation of odd-chain FAs
conversion of propionyl CoA to succinyl CoA requires B7 (for propionyl CoA carboxylase) and B12 (for methylmalonyl mutase)
what happens when there’s a deficiency in methylmalonyl mutase (B12 metabolism)?
results in methylmalonic acidemia (accumulation of methylmalonyl CoA, BCAA, thr, OCFA, VOMIT)
infants begin to develop symptoms when first introduced to solid foods or with first viral or bacterial infection (because this triggers fasting state which will result in protein catabolism)
treatment = low protein diet (decrease protein catabolism), often supplemented with B12 or carnitine
what are met and thr degraded to?
they’re degraded to alpha-ketobutyrate which is converted to propionyl CoA
met –> homocysteine (add serine) –> cystathionine, cysteine is released via PLP; deamination of thr–> alpha-ketobutyrate –> propionyl CoA
rxn of alpha-ketobutyrate –> propionyl CoA is similar to the reaction catalyzed by pyruvate dehydrogenase and alpha-KG dehydrogenase (uses coenzymes TPP, lipoic acid, CoA, FAD, NAD+)
how is met made from homocysteine?
via met synthetase using B12 and tetrahydrofolate-CH3
homocysteine is methylated by FH4-CH3, using B12 as a cofactor –> converts to met
what are the branched amino acids and what are they degraded to?
val, ile, and leu
VAL is degraded to propionyl CoA, ILE to propionyl CoA and acetyl CoA, LEU to acetyl CoA and acetoacetate also ONLY ONE OF TWO AAs THAT IS SOLELY KETOGENIC
about 20% of AA in proteins are branched chain, and BCAAs have lots of oxidizable carbon so they play a large role in ENERGY PRODUCTION in fasting state
explain the reaction of BCCAs
val, ile, and leu are all first transaminated (reversible) and then undergo oxidative decarboxylation via branched chain alpha-ketoacid DH
deficiency in alpha-ketoacid DH results in MAPLE SYRUP URINE DISEASE –> build up of BCAAs
what is the maple syrup urine disease?
MSUD is caused by deficiency in branched-chain alpha-ketoacid DH
acute PRESENTATION occurs when protein catabolism INCREASES due to fasted metabolism or consumption of BCAAs
what can alpha-ketoisocaproic acid trigger?
derived from leu and triggers neuronal apoptosis
leu, ile, and val compete with other large neutral AA (like phe and trp) for entry into brain –> leads to depletion of AA needed for neurotransmitter synthesis
what are the treatments for MSUD?
based on prevention of acute episodes and remediation of neural AA deficits (reversal of catabolic state; IV glucose initially then high calorie intake)
prevention of acute episodes
- tight regulation of BCAA consumption
- weekly AA monitoring
- early detection and treatment of infections or other physiologic stresses
remediation of neural AA deficits
- supplementation with tyr, trp, met, phe, his, thr, gln
what is organic aciduria?
inherited disorders caused by deficiencies in enzymes involved in AA carbon skeleton degradation
alpha-ketoacids accumulate and contribute to development of metabolic acidosis, hyperammonemia, and neurologic damage
what is the presentation of organic aciduria?
acute presentation with metabolic compensation = vomiting, metabolic acidosis, hypoglycemia, hyperammonemia (some cases it’s caused by inhibition of N-acetylglutamate synthase which makes N-acetylglutamate that activates CPSI)
what are the long-term consequences of organic aciduria?
developmental delay, ataxia, heart, kidney, and pancreatic problems
what are the treatments of organic aciduria?
- restriction of triggering AA (branched AA)
- avoidance of fasting and monitoring of illness
- supplementation with carnitine or glycine to facilitate production and elimination of acid-conjugates
- vitamin supplementation
- treatment of hyperammonemia as needed
what is the function of ketogenic AAs?
they produce acetyl CoA or acetoacetate
trp catabolism is complex – it can be converted to nicotinamide portion of NAD/P, it’s ketogenic (acetyl CoA) AND glucogenic (can be converted to alanine –> pyruvate –> glucose), also generate formate
lys –> acetyl CoA
thr has two metabolic routes – one generates propionyl CoA via alpha-ketobutyrate and another generates glycine and acetate/acetyl CoA
what happens when there’s defects in phe and tyr catabolism?
associated with many diseases
phe is hydroxylated to tyr by PHENYLALANINE HYDROXYLASE –> deficiency in hydroxylase or cofactor (tetrahydrobiopterin) results in phenylketouria (PKU)
tyr aminotransferase also transaminates phe, explaining accumulation of phenylketone in PKU
what is the function of homogenitsate oxidase?
phe –> tyr via phe hydroxylase –> hydroxyphenylpyruvate –> homogentisate via decarboxylation –> fumarate and acetoacetate via homogentisate oxidase
deficiency in homogentisate oxidase result in ALKAPTOURIA
what is the difference between classic and nonclassic PKU?
classic = deficiency in phe hydroxylase
nonclassic = deficiency in cofactor tetrahydrobiopterin (BH4)
what can PKU cause?
accumulated phe inhibits transport of other large hydrophobic AAs to brain, causing altered neurotransmitter synthesis leading to problems in PSYCHOMOTOR development
decreased synthesis of CATECHOLAMINES may cause mood disorders in older patients
phenylpyruvate (phenyllactate and phenylacetate) , produced by transamination of phe, accumulates in serum and urine (musky or mousy odor)
what is tyr a precursor for?
tyr is precursor of melanin (lack of melanin results in albinism)
what is the treatment for PKU?
restriction of dietary phe and sometimes supplementation with large hydrophobic AAs
nonclassical PKU can be treated with TETRAHYDROBIOPTERIN which can also benefit some individuals with classic PKU
what is alkaptonuria?
results from deficiency in homogenitsate oxygenase
accumulation of homogentisic acid in urine causes it to turn black upon air oxidation
over time –> homogentisic acid accumulates in various body fluids/tissues, causing large joint arthritis and black pigmentation (ochronotic)
how is tetrahydrofolate made?
synthesized from folic acid and requires dihydrofolate reductase to convert from folate –> dihydrofolate –> tetrahydrofolate (cofactor for serine hydroxymethyl transferase and glycine cleavage enzyme)
folate has 3 parts – pteridine ring, PABA, and glutamate
what are sulfa drugs and their significance?
they’re used to treat certain bacterial infections
analogs of p-aminobenzoic acid (PABA)
substrate for synthesis of folic acid in bacteria (inhibit synthesis of folic acid in bacteria –> necessary for growth and reproduction)
what is the most OXIDIZED form of tetrahydrofolate?
formyl-tetrahydrofolate
what is the most REDUCED form of tetrahydrofolate?
methyl-tetrahydrofolate
what is the IRREVERSIBLE step in the oxidation of tetrahydrofolate?
methylene-tetrahydrofolate to methyl-tetrahydrofolate
what is important about the carbon which tetrahydrofolate carries?
it is used in the synthesis of many biomolecules like nucleotides and neurotransmitters
what happens when there’s a folate deficiency in pregnancy?
can lead to neural tube defects
what happens to the fully methylated form of tetrahydrofolate?
the ONLY possible fate is donation of methyl group to homocysteine to make methionine
methyl-tetrahydrofolate transfers its methyl group to homocysteine via met synthetase using B12 as cofactor –> forms met – formation of the methyl species for this reaction is IRREVERSIBLE
what AAs use tetrahydrofolate?
- serine via serine methylhydroxy transferase
- glycine via glycine cleavage enzyme
- histidine
- tryptophan
describe the activated methyl cycle
methyl-tetrahydrofolate donates its methyl group to B12, methylated B12 is donated to homocysteine to make met via met synthetase (note: deficiency in methyl-hydrofolate can disrupt this cycle)
met is used in protein synthesis or to generate S-adenosylmethionine (SAM) using ATP –> SAM dontas methyl group to various molecules, generating S-adenosylhomocysteine (SAH) which is cleaved to form homocysteine and adenosine (homocysteine can be used to make cysteine or met)
Some molecules that SAM donates methyl group to are norepinephrine to make epinephrine, nucleotides to make methylated nucleotides
what does a deficiency in MTR (met synthetase) cause?
Type II homocysteinEMIA
recall cystathionine beta-synthetase deficiency causes homocystinURIA
what is B12?
cobalamin
complex molecule synthesized only in bacteria –> humans obtain B12 from animals –> animals obtain them from bacteria
structural similarity to heme, also coordinated by porphyrin ring and adenosyl group (X group that ligand binds to can be CN, CH3, or 5’-doxyadenosine)
what are the only two enzymes in humans that use B12?
methionine synthetase and methylmalonyl mutase
what happens when there’s a deficiency in B12?
disrupts the activated methyl cycle and ELEVATED methylmalonic acid levels –> this is important in determining whether it is a B12 or B9 deficiency
B12 = methylmalonyl CoA mutase
B9 and B12 = met synthetase
can also result in macrocytic anemia and neurological dysfunction
what is the cause of pernicious anemia?
caused by genetic or age-related problems with dietary B12 absorption
explain the absorption and transport pathway of B12
dietary B12 is bound by R-binders (salivary and gastric proteins) as it passes through the stomach
intrinsic factor (another gastric protein) binds to B12 in intestine, after R-binders are degraded (DEFICIENCY in intrinsic factor is PRIMARY cause of pernicious anemia because intrinsic factor is important in absorption of B12) –> in ileum, B12-intrinsic factor complex is taken into enterocytes by specific receptors
in enterocytes, B12 forms complexes with transcobalamin II which transports 50% to tissues and 50% to liver which stores enough B12 to supply the body’s needs for 3-6 years (B12 deficiency doesn’t become symptomatic until 3-6 years after store begins to deplete)
what happens in B12 deficiency resulting in anemia?
anemia associated with B12 deficiency is due to depletion of METHYLENE-FH4 which is required for nucleotide biosynthesis
deficiency results in defects in erythrocyte development and bone marrow releases megaloblasts
methylene to methyl is an irreversible step that can lead to depletion of methylene and increase methyl that is stuck as methyl-tetrahydrofolate (METHYL TRAP) because there’s no B12 to catalyze met synthetase
build up of methyl-tetrahydrofolate can also create SECONDARY FOLATE DEFICIENCY because the body will be low on folate since it’s stuck as methyl-tetrahydrofolate
what happens in B12 deficiency resulting in neurological deficiency?
can cause peripheral neuropathy, professing to spastic gait disturbance
B12 deficiency due to depletion of SAM (required for the synthesis of some neurotransmitters)
accumulation of methylmalonyl CoA in nervous system is also thought to be contributing factor
recall: how is tyrosine made?
derived from phenylalanine in a BH4 (tetrahydrobiopterin) dependent reaction catalyzed by phenylalanine hydroxylase
recall: how is PKU caused?
deficiency in conversion of phe –> tyr – either in hydroxylase or metabolism of BH4 (tetrahydrobiopterin)
explain the process of generating tetrahydrobiopterin (BH4) and its use in phenylalanine hydroxylase
BH4 is synthesized from GTP –> it’s oxidized with phe, each providing 2 elections for reduction of O2 –> generates tyr and dihydrobiopterin –> BH2 is reduced back to BH4 using DIHYDROPTERINE REDUCTASE
what are the catecholamines?
dopa, dopamine, norepinephrine, and epinephrine are all synthesized from tyr
explain the process of generating catecholamines
phe generates tyr via phe hydroxylase –> tyr is hydroxylated to dopa via tyr hydroxylase (uses BH4 as a cofactor) –> dopa is decarboxylated to dopamine in the neuron via dopa decarboxylase (uses PLP/B6 as a cofactor) –> dopamine is hydroxylated by dopamine beta-hydroxylase (mixed function oxidase) that requires Cu+2 and vitamin C (deficiency of vitamin C = scruvy, microcytic anemia, and this reaction) to norepinephrine
in adrenal medulla, norepinephrine is methylated using SAM which then generates epinephrine (adrenal medulla releases primarily epi but also some norepi)
explain Parkinson’s disease
substantia nigra in the brain controls movement
Parkinson’s disease - dopaminergic cells in the substantia nigra STOP producing dopamine –> as these cells die, brain does not receive necessary messages for movement
symptomatic relief from Parkinson’s is obtained by administration of L-dopa which is the precursor for dopamine –> this helps the enzyme work faster and generate more dopamine
how do recreational stimulants affect dopamine?
it inhibits the reuptake of dopamine in specific regions of the brain, increasing the synaptic gap levels of dopamine – prolonging its effects
how do schizophrenia and ADHD affect dopamine?
schizophrenia is linked to an OVERPRODUCTION of dopamine
ADHD is linked to REDUCED levels of dopamine
