NB3-1 - Biochemical Integrative Metabolism: Neurotransmitters from Amino Acids

Question 1

What mnemonic is useful for remembering the essential amino acids? How about for which amino acids are basic, ketogenic, and branched?

Answer 1

Question 2

How is carbon monoxide synthesized in vivo? What effects does CO have as a NT?

Answer 2

CO is produced by heme oxygenase during heme degradation. CO, similar to NO, will stimulate synthesis of cGMP and activation of protein kinase G.

In low concentrations, CO is neuroprotective

Question 3

List the amino acids that are NTs themselves then list the NTs we need to know that are derived from NTs.

Answer 3

NT amino acids - glutamine, glutamate, aspartate, and glycine

NTs derived from amino acids:

GABA from glutamate

Dopamine from tyrosine

Serotonin from tryptophan

Question 4

Answer 4

Question 5

What is the GABA shunt for and how does it work?

Answer 5

The GABA shunt is a way to recycle GABA. It involves transaminating GABA with α-KG to produce glutamate and another molecule that can be readily converted into succinate which can enter the TCA cycle.

Question 6

Describe the reaction that produces GABA from glutamate

Answer 6

Glutamate decarboxylase utilizes Vit B6 (PLP) to decarboxylate glutamate to GABA

Question 7

Describe how a neuron gets glutamate from molecules that can pass the BBB.

Answer 7

1. Leucine, Isoleucine, Valine, and ammonia can pass the BBB and enter astrocytes
2. Astrocytes utilize transaminases to convert a BCAA (branched chain amino acid) and α-KG into glutamate and a BCKA
3. Glutamine synthetase is then used to aminate glutamate using NH4 into glutamine
4. Glutamine is transported out of the astrocyte and into the neuron where glutaminase deaminates it back to glutamate

Question 8

What is often used to treat epilepsy and why?

Answer 8

GABA analogs or drugs that block GABA reuptake

This is because epilepy if often associated with low GABA

Question 9

How does valium work? What is the chemical name for valium type drugs?

Answer 9

Benzodiazepines (valium) work by binding to the GABA receptor and potentiating (increasing the power of) GABA. This reduces anxiety

Question 10

Describe how a cell gathers the choline needed to synthesize ACh.

Answer 10

The nitrogen from an amino acid is transferred to a phospholipid to form PE (phosphatidylethanolamine). PE is then methylated three times to form PC (phosphatidylcholine) by SAM utilizing THF (folate) and Vit B12 (cobalamin). PLD (phospholipase D) can then cleave the choline off of PC.

Choline can also be taken back up from a synapse after ACh has been degraded by AChesterase

Question 11

What enzyme combines acetyl-CoA and choline into ACh?

Answer 11

Choline acetyltransferase

Question 12

Answer 12

A

Question 13

Answer 13

C

B12 is used by methylmalonyl-CoA mutase to clear the body of methylmalonate

Question 14

List the steps involved in the synthesis of melatonin. Include enzymes, substrates, and cofactors.

Answer 14

1. Tryptophan hydroxylase hydroxylates tryptophan to 5-hydroxytryptophan (5-HTP) using tetrahydrobiopterin (BH4) as a reducing agent. BH4 is oxidized to dihydrobiopterin BH2 in the process and must be reoxidized to BH4 by BH2 reductase using NADPH from the PPP.
2. 5-HTP decarboxylase utilizes PLP (Vit B6) to decarboxylate 5-HTP to 5-hydroxytryptamine (Serotonin, 5-HT)
3. An acetyl- and methyltransferase are then used to convert serotonin to melatonin

Question 15

List the steps involved in the synthesis of epinephrine. Include enzymes, substrates, and cofactors.

Answer 15

1. Tyrosine hydroxylase, using BH4 as a reducing agent, hydroxylates tyrosine to 3,4-Dihydroxyphenylalanine (L-DOPA). BH2 is reoxidized to BH4 by BH2 reductase and NADPH
2. DOPA decarboxylase decarboxylates DOPA to dopamine
3. Dopamine ß-hydroxylase, utilizing ascorbate (Vit C) as a reducing agent, hydroxylates dopamine to NE
4. Phenylethanolamine-N-methyltransferase (PNMT), utilizing SAM, methylates NE to epinephrine

Question 16

Where does a cell that synthesizes L-DOPA get its tyrosine from?

Answer 16

Either from the diet or it uses phenylalanine hydroxylase (PAH) and BH4 to hydroxylate phenylalanine into tyrosine

Question 17

What is another name for Vit B1? Why is B1 important to neurotransmitter synthesis in the brain?

Answer 17

Thiamine Pyrophosphate (TPP) is crucial to keeping the PDH complex and krebs cycle running which, in turn, provides brain cells with ATP and substrates needed for NT synthesis.

Question 18

What is maple syrup urine disease?

Answer 18

It is a genetic metabolic disorder where the branched chain amino acid dehydrogenase complex (BCAA DH) is deficient in some way. This renders the body unable to metabolize BCAAs (leucine, isoleucine, and valine) and for the BCAAs to build up in the body. This leads to bodily excretions smelling sweetly, hence the name.

Question 19

What is the best way to assess vit B1 levels?

Answer 19

Do a transketolase activity assay

Question 20

What is another name for Vitamin B12? Why is this vitamin important to the formation of NTs?

Answer 20

Cobalamin (B12) and methyl-THF are required to regenerate methionine from homocysteine. Methionine is then used to make SAM which is needed to form choline. Choline is needed to make ACh. SAM is converted into homocysteine when making choline. Without B12, all the SAM would eventually get trapped as homocysteine.

Question 21

Why is methyl-tetrahydrofolate important to NT synthesis?

Answer 21

mTHF is used, along with cobalamin, to regenerate SAM from homocysteine. SAM is then used to form choline which is used to form ACh. Without mTHF, SAM would deplete and homocysteine would accumulate

Question 22

What are the overall effects of ammonia on the nervous system (stimulant or depressant)? What is the major theory as to why this is?

Answer 22

Ammonia appear to have a stimulating effect on the nervous system.

This is believed to be because an excess of ammonia drives the formation of glutamine instead of GABA from glutamate (refer to image). GABA is inhibitory and glutamine will be used to make more glutamate, which is excitatory. This is why it is thought an ammonia accumulation causes hyperexcitability in the nervous system