Unit 2-2 Metabolic (Protein and Diet) Flashcards
AA basics and categorization
basics- 20 AAs
have own tRNAs to be translated into proteins
-many post-translationally modified
based on chemical features- acidic or basic, P or NP
chemical constituents
essential- need from diet
nonessential- can be made from others
conditionally essential- limited capacity for synthesis
based on C skeletons: categorizes outcome of the veto acid
Glucogenic: AAs can be used in gluconeogenesis
-prod pyruvate or Kreb cycle intermediate
Ketogenic: AAs can generate Acetyl CoA then prod E via TCA cycle or ketone bodies
Burned off as CO₂- can’t be in gluconeogenesis
-ONLY leucine + lysine
protein breakdown process
-enzyme type
process
2 breakdown pathways
via peptidases
- need to be activated
- categorized by type of enzyme and the bond they cleave
- break down long peptide chains to AAs to be abs into circ
process
receptors/enzymes/transcription factors made after gene transcription and translation
chromatin unwinds
transcription factors and RNA polymerase make template RNA for translation
2 breakdown pathways
ubiquination
-targets protein for degradation in proteasomes
(ATP dependent)
degradation in lysosomes
-engulf EC proteins or pathogens and hydrolyze
(ATP Independent)
transamination process
Transamination
done by aminotransferases
-convert alpha-keto acid to AA, and in process convert another AA to an alpha-keto acid
reversible; Keq ~1
100s of aminotransferases each selective for few AAs
2 specific aminotransferases: AST and ALT
(PLP from Vit B6 used by aminotransferases to hold/transfer N groups)
NH2 has to be removed from AA to be used for gluconeogenesis
NH2 added to C skeleton to make AA
rxns typically in liver
also kidney, intestine, muscle
prototypical rxn:
AA donates NH2 to alpha-ketogluterate to prod L glutamate and an alpha keto acid via aminotransferase
NH3 then released w/ regeneration of alpha ketogluterate
-NH3 is toxic; needs to leave via urea synthesis
urea cycle process
overall rxn:
3ATP + HCO3- + NH4+ + aspartate –> 2ADP + AMP + 2Pi + PPi + fumarate + urea
part in cyto, part in mito
ornithine is recycled in urea cycle:
Aspartate, free NH3
transaminated urea converted to carbamoyl phosphate via carbamoyl phosphate synthase 1
-1st key regulated step in protein catabolism
N from carbamoyl phosphate enters urea cycle, ultimately combined w/ NH3 from aspartate –> urea (2N)
urinary N in form of urea then represents marker of AA catabolism and oxidation
glutamine and arginine significance w/ N
Glutamine
important 2N containing AA
accepts N from other AAs in peripheral tissue, carries to liver/kidney
donates to glutamate
then glutamate to alpha ketogluterate via glutamate dehydrogenase
-2nd key regulated step in protein catabolism
Arginine
minor pathway for N removal via prod of NO
special AAs
sulfur containing- 2
aromatic AAs- 3
sulfur containing
cysteine: disulfide bridges that change protein conf
methionine:
- S-adenosylmethionine SAM
- E source for rxns, methyl donor
- precursor for homocysteine (vascular disease, wound healing, B12/folate metabolism)
- glutathione-
- tripeptide containing cysteine
- redox buffer
- protects against free radical injury
aromatic AAs
tryptophan, phenylalanine, tyrosine
precursors for serotonin, niacin, DA, NE, tetrahydrobiopterin BH4, TH
scurvy
define
signs/symptoms
Vit C role
dec collagen strength from lack of Vit C -pale skin loss of teeth sunken eyes dec vascular endothelium--> hemorrhages --> loss of RBCs (swollen gums, bruising, anemia)
Vit C is req coenzyme for hydroxyproline and hydroxylysine for collagen strength
Vitamin C, K, B6 cofactors
Vitamin C
o Coenzyme for Hydroxyproline and Hydroxylysine in collagen strength
o Pro–>Hyp via prolyl hydroxylase and Vit C
o Lys–>Hyl via lysyl hydroxylase and Vit C
Vitamin K
o Coenzyme to target proteins to membranes via Ca chelation
o Glu–>Gla via G-glytamyl carboxylase and Vit K
Vitamin B6 (PLP) o Precursor to Pyridoxal Phosphate PLP o Used by aminotransferases to hold/transfer amino groups in transamination
proteases
break down proteins into respective AAs
initially zymogens
Pepsin: stomach
pepsinogen cleaved by HCl
cleaves proteins
Enteropeptidase: intestine
activated by several, incl trypsin
cleaves trypsin
trypsin: pancreas to SI
trypsinogen cleaved by enteropeptidase to prod trypsin
trypsin cleaves all other zymogens
urea cycle and control points
o Ornithine–> Citrulline (catalyzed by Carbamoyl phosphate synthetase I )
o Citrulline + Aspartate–> Argininosuccinate (catalyzed by Arginonosuccinate synthase)
o Argininosuccinate–> Arginine (catalyzed by Argininosuccinate lyase)
o Arginine–> Ornithine + Urea (catalyzed by Arginase)
Carbamoyl phosphate synthetase I (initial step in Urea Cycle entry)
o Important urea cycle enzyme found in mitochondria.
o Rxn: HCO3- + NH3 carbamoyl phosphate
♣ uses 2 of the 3 ATPs in urea cycle.
o N-acetylglutamate is an allosteric activator of Carbamoyl phosphate synthetase I.
♣ Arginine is an activator of N-acetylglutamate synthase
• Catalyzes acetyl CoA + glutamate to N-acetylglutamate
transport of ammonia through he blood
can’t be transported through blood
most tissues:
glutamate –> glutamine via glutamine synthase
2Ns on glutamine transported to liver for urea cycle
muscles:
use alanine to transport into alanine-glucose cycle
(Pyruvate buildup from glycolysis can be –> alanine then go to liver, then back to pyruvate, and glucose can be made and delivered back to muscle)
Glu dehydrogenase: control point for protein metabolism
-controls direction of N removal or incorporation into AAs
Arginine in nerve and muscle func
cross talk and alt rxns related to urea cycle
Arginine –> citrulline via NO synthase
-prod NO NT
Arginine –> ornithine via arginase in urea cycle
or, catalyzed –> creatine phosphate for muscle E
hyperammonemia
ammonia accumulation- depletes alpha-ketoglutarate- inhibits TCA cycle
acute: tremor (asterixis**) encephalopathy seizures, ataxia, visual loss, hallucinations, mania vomiting, loss of appetite neonates: temp instability, hypervent
chronic: dev delay nausea, failure to thrive, protein avoidance migraines anxiety, depression, disinhibition hepatomegaly, elevated LFT's
triggers: illness, fever, vomiting, fasting, surgery postpartum period**, menarche intense exercise dietary protein load meds- valproate, peg asparginase UTI
tx: limit protein intake
Maple syrup urine disease MSUD
BCKCD complex deficiency
build-up of alpha keto acids in urine (sweet smell), but even more conc in earwax
branched chain AAs-
Isoleucine, Leucine, Valine
first, branched chain AAs are deaminated by aminotransferases –> alpha keto acids
then decarboxylated by BCKCD
common in Amish broad spectrum severe neonatal: irritability and poor feeding at 48hrs lethargy, opisthotonus, apnea cerebral edema, encephalopathy (Leucine accum in brain) reversible w/ tx
(I live Vermont maple syrup from b1anches)
Dx High leucine urine ketones in neonate gene sequencing: BCKDCD, DBT, DLD Diagnostic: allo-isoleucine present
Tx
thiamine supplementation
limit dietary protein
leucine-free formula, regular serum leucine levels
close monitoring of nutritional status (esp Isoleucine and Valine)
consider liver Tx
leucine is likely teratogenic
thyroid chemistry
Tyrosine used to make T4
T4 used to make T3
TSH stimulates iodide uptake and release of T4,T3
Thyroid peroxidase: oxidizes Iodide to I2
Thyroglobulin Tg: contains Tyr residues iodinated to form T4,T3
Thyroxin binding globulin TBG: transports T4,T3
Heme metabolism
porphyrias
degradation
jaundice
Porphyrin/heme metabolism:
porphyrin production:
Gly + succinyl CoA –> delta-aminolevulinic acid (ALA) via delta-aminolevulinate synthase
2x ALA –> porphobilinogen via delta-aminolevulinate dehydratase
Porphobilinogen ———-> Protoporphyrin IV via 4 enzymes
Protoporphyrin IX –> heme via ferrochelatase
derived from Gly and TCA intermediates
cyclic, made of 4 pyrroles
primarily prod in liver
binds Fe2+
porphyria- disease in porphyrin synthesis
Lead poisoning
Lead inhibits 2 enzymes for porphyrin synthesis
delta-aminolevulinate deydratase and ferrochelatase
degradation Heme --> biliverdin (green) --> bilirubin (red/orange) --> bilirubin diglucuronide --> urobilinogen --> sterocobilin (Brown)
bilirubin transported to blood via Albumin
in liver: bilirubin conjugated w/ glucuronic acid –> bilirubin diglucuronide (AKA conjugated)
in intestine: bilirubin diglucuronide oxidized –> setercobilin
jaundice: bilirubin can’t be processed properly
hemolytic jaundice- too many RBCs lyse
neonatal jaundice: conj bilirubin not prod fast enough (low leaves of bilirubin glycuronyltransferase)
cysteine
unessential AA
synthesized from Met
can form disulfide bonds w/ other cysteine –> cystine (oxidized)
-folding and structure importance
Glutathione GSH
highly soluble tripeptide that uses -SH buffer to maintain proteins in reduced form (ex - reduced heme for functional Hgb)
-controls redox pot of GSHGSSG (cysteine actually is the worker)
-protect against ROS
Methionine
essential AA
used to prod SAM, an intermediate in production of cysteine
SAM:
prod in 1st step of Met degeneration w/ ATP
-activated sulfur: roles in epigenetic, host defense, DNA methylation, maternal diet, depression tx, etc
-AKA adoMet
-major C donor; high E storage unit
2 Met options:
Met–>SAM–>SAH –> homocysteine –> Met
needs coenzymes THF and Vit B12 to transfer back CH3 group and methionine synthase
Met –>SAM –> SAH –> homocysteine –>cystathionine –> cysteine
hyperhomocysteinemia
multiple problems incl CVD
from low folate, B6, and B12 (vascular disease)
cysteine is now essential
Tx w/ folate, B6, B12
homocystinuria
(AR) defect in cystathionine-B-synthase CBS
can’t convert homocysteine to cystathionine (and eventually cysteine)
inc homocysteine has toxic effect on tissue (skeleton, eye, vasculature) and high risk of thrombotic events
Clinical presentation: mental retardation, osteoporosis, scoliosis, vascular disease, thrombosis, Marfanoid habitus (AD) (other lecture says pectus carinatum??), lens subluxation (down and in) high homocysteine in urine*
Treated pts will get osteoporosis, vascular risk
cysteine is now essential
Dx w/ elevated Hcy, need to methionine, methylmalonic acid, and B12 level
CB sequencing
Tx w/ Vit B6 to “force” CBS activity
mainstay tx is restrict methionine diet and Betaine
pts often on coumadin/anticoagulant
avoid smoking and OCPs
cystinuria
kidney stones (renal failure) defective transporter of cysteine (and ornithine, lysine, arginine- "COLA") that leads to crystallization in urea
tx w/ acetazolamide that makes cysteine more soluble (and hydration)
vascular disease
autoimmune disease where Hcy acts as a pro-inflammatory molec
B6, B12, folate in Cys and Met metabolism
B6:
homocysteine –> cysteine via CBS
B12:
homocysteine –> Met via Methionine synthase
Folate:
makes THF via DHFR
involved w/ 1-C transfers
homocysteine –> Met via Methionine synthase
Trp metabolism products
Trp –> pyruvate or acetyl CoA
Trp hydroxylated by tryptophan hydroxylase via BH4 cofactor to prod DOPA
then DOPA –> catecholamines (DOPA, DA, NE, EPI) and melanin
Trp used to prod serotonin, melatonin, and niacin