lecture 13: choline Flashcards
CHTs
choline transporter
high affinity, saturable, sodium dependent, provide choline for acetylcholine synthesis in the presynaptic nerve terminal
main form of choline in food and body
PtdCho, phospholipid with choline as polar head group, member of lecithin (amphipathic)
made by CDP-choline pathway or PEMT pathway
low affinity sodium independent choline transporters
provide choline for phospholipid synthesis
metabolism of choline
liver
1) phospholipid biosynthesis
2) conversion to methyl donor betaine
neurons: converted to acetylcholine
PtdCho in liver can be used for…
membrane biogenesis
formation of bile
secretion in VLDL (VLDL transports it)
PEMT pathway
makes choline from another precursor molecule
PE (non-choline substrate) > PtdCho via PEMT via 3 steps
methyl donor = AdoMet
CDP-choline pathway
produces most of the PtdCho
impairment leads to apoptosis
begins with choline
1) free choline phosphorylated by CK
2) phosphocholine activated to CDP choline (rate limiting, catalyzed by CT)
3) CDP choline + DAG via CPT > PtdCho
CT enzyme and regulation
activates phosphocholine to CDP choline
translocates to nuclear membrane in response to increased demand for PtdCho (PtdCho degredation, FAs, DAGs)
inactive soluble form and active membrane-bound form
activating lipids/PtdCho depletion increases membrane lateral packing stress > insertion of CT into membrane bilayer
packing stress
activating lipids or PtdCho depletion increases membrane lateral stress > CT binding
how is PtdCho made?
CDP-choline pathway or PEMT pathway
PEMT pathway
sequential methylation of non-choline substrate PE > PtdCho
all steps catalyzed by PEMT
methyl donor = AdoMet
methyl donors
methyl donors form AdoMet, which is formed from folate (methyl cycle) or betaine (oxidation of choline)
Acetylcholine
neurotransmitter, controls output of many organs
choline acetyltransferase (ChAT)
in the neuron, choline not used for PtdCho is used for acetylcholine synthesis
choline + acetyl-CoA > acetylcholine
acetylcholine production
in neuron, choline not used for PtdCho is acetylated by ChAT to generate acetylcholine
acetylcholine packaged into synaptic vesicles
acetylcholine released into post-synaptic cleft
AChE: acetylcholine > acetate + choline (choline is recycled)
where does free choline for acetylcholine synthesis come from?
low affinity transporter from blood transports free choline to neuron, high affinity transporter in neuron for recycling > formation of PtdCho or enter acetylcholine cycle
PtdCho can also be hydrolyzed by phospholipase D to free choline for acetylcholine biosynthesis
choline deficiency
fatty liver and liver dysfunction are main clinical manifestations
PtdCho secreted in VLDL
Choline deficiency = inability to removed fat being produced in the liver
why is it that fatty liver and liver dysfunction would be the main symptoms of choline deficiency?
VLDL PRODUCTION
transporter of lipids is not being excreted, it needs the PtdCho
can’t transport lipids in the liver without VLDL
inability to remove fat being produced in the liver
what is free choline soluble in?
water soluble
If CT translation is inhibited, how could choline still be involved in the production of PtdCho?
PEMT pathway
Choline can be transferred to mitochondria, oxidized to betaine, which is then released back to the cytosol to serve as the methyl group donor for PEMT pathway
donated to AdoMet, activated methyl group
How might folate contribute to the production of PtdCho?
PEMT pathway
Folate provides the methyl groups necessary to Adomet → carry out sequential methylation reactions in PEMT → PtdCho
methyl donor is either folate or betaine
