day16 bioc

reasons for protein turnover

heat, oxidation, UV

main pathways of protein degradation

ubiquitin-proteasome system (UPS) and lysosome

E1

activates Ub and transfers to E2

E2

transfers Ub to E3

E3

ubiquitinylates target protein

poly-Ub

one site with chain of Ub - degradation

deubiquitylation enzymes

removes and recycles Ub from mouth of proteasome

mono-ubiquitylation of cell surface receptor

promotes endocytosis and degradation over recycling

mannose-6-phosphate (M6P)

lysosomal localization signal

Gaucher

glucocerebrosidase

Fabry

α-galactosidase

Tay-Sachs

hexosaminidase

Nieman-Pick

acid sphingomyelinase

Pompe

α-glucosidase

transmination substrates

α-ketoglutarate, glutamate

action of glutamate dehydrogenase

glutamate → α-ketoglutarate + NH₄⁺

carbamoyl phosphate synthase I (CPS I)

MITOCHONDRIA: NH₃ + CO₂ + 2 ATP → carbamoyl phosphate, needs N-acetylglutamate

ornithine trans-carbamoylase

MITOCHONDRIA: ornithine + carbamoyl phosphate → citrulline

arginase

CYTOSOL: arginine → urea + ornithine

histamine

histidine decarboxylase; H1-H4 GPCRs

H1 GPCR

vasodilation, bronchoconstriction

H2 GPCR

secretes HCl into gastric lumen

GABA

glutamate decarboxylase with Vit B6 (pyrodoxine); inhibitory action on neurons

serotonin

tryptophan involving tetrahydrobiopterin and Vit B6; degraded to 5-HIAA via MAO

nitric oxide (NO)

made from hydroxyarginine; activates guanylyl cyclase (smooth muscle relaxation)

T4

tetraiodothyronine (inactive form)

T3

triiodothyronine (active form)

thyroid peroxidase

oxidizes I- to I, enabling addition to thyroglobulin

pendrin

anion channel that secretes I from thyroid

catecholamine synthesis

tyrosine hydroxylase + aromatic decarboxylase converts tyrosine → DOPA → dopamine

degradation of norepinephrine, epinephrine, dopamine

catechol-O-methyltransferase (COMT), monoamine oxidase (MAO)

use of L-DOPA in Parkinson’s

crosses BBB

creatine phosphate

stores energy; converts ADP to ATP when needed quickly

creatinine

formed from spontaneous dehydration of creatine phosphate; reflects muscle mass and kidney function

glutathione

neutralizes free radicals and oxidative stress (reduced form highly present in cytosol)

phenylalanine hydroxylase

Phe → Tyr

presentation of phenylketonuria

pale skin and hair (no tyrosine for melanin)

homocystinuria

Cysteine with one extra carbon R chain; excess is excreted in urine (cysteine not made via CBS)

ALA synthase

glycine + succinyl CoA → ALA (inhibited by heme)

molecular consequences of heme deficiency

increased porphyrin precursors, porphyrins, and oxidized forms

lead poisoning

inhibits ALA dehydratase and ferrochelatase

acute intermittent porphyria

autosomal dominant in porphobilinogen deaminase

porphyria cutanea tarda

chronic porphyria of skin not helped by sunscreen; uroporphyrinogen III decarboxylase

why are bruises colored

heme degradation: biliverdin (green), bilirubin (red-yellow), hemoglobin (red-blue)

UDP-glucuronosyl transferase

makes bilirubin more water soluble

MRP3

pumps bilirubin back into blood

MRP2

pumps bilirubin glucuronide into biliary canaliculi

bililights

converts bilirubin from Z-Z to soluble E-E isomer

Rh factor

transmembrane proteins in blood