One Carbon Metabolism

Question 1

Amino Acid Derived Compounds of Biologic Importance

Answer 1

• Dopamine- tyrosine precursor, neurotransmitter
• Epinephrine- tyrosine precursor, hormone
• GABA- glutamate precursor, neurotransmitter
• Histamine- histidine precursor, vasodilator
• Melanin- tyrosine precursor, pigment
• Melatonin- tryptophan precusor, hormone
• Norepinephrine- tyrosine precursor, neurotransmitter
• Serotonin- tryptophan precursor, vasoconstrictor
• Niacin-tryptophan precursor, hormone

Question 2

Formative of Dopa

Answer 2

• tyosine is hydroxylated to 3,4-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase, a mixed- function oxidase,which requires tetrahydrobiopterin as a cofactor
• tyrosine hydroxylation is the rate-limiting step in catecholamine biosynthesis; the enzyme is allosteric, with dopamine, norepinephrine, and epinephrine acting as negative effectors

Question 3

Parkinson’s and dopa

Answer 3

• Parkinson’s is caused by a death in the dopamine producing cells in the brain
• patients are give DOPA since it will cross the blood brain barrier and hopefully increase the production of dopamine
• more substrate means more product

Question 4

Formation of dopamine

Answer 4

-aromatic amino acid decarboxylase, a pyridoxal phosphate-dependent enzyme, forms 3,4-dihydroxyphenyethylamine (dopamine) from dopa

Question 5

Formation of norepinephrine

Answer 5

• another mixed function oxidase, dopamine B-hydroxylase, hydroxylates dopamine on the side chain to yield norepinephrine
• the enzyme contains copper and requires ascorbate (vitamin C) and molecular oxygen
• norepinephrine is the major neural transmitter of the sympathetic nervous system

Question 6

Formation of epinephrine

Answer 6

-norepinephrine is methylated by phenylethanolamine N-methyltransderase to form epinephrine, using SAM as methyl donor

Question 7

Catechol Degradation

Answer 7

• degraded by an enzyme called monoamine oxidase
• inhibitors of MOA are used as antidepressants
• the dopamine pathway continues to be the site of development of many new drugs

Question 8

Biosynthesis of melanins

Answer 8

• biological pigments
• the synthesis of melanins occurs only in pigment-producing cells called melanocytes. In these cells, melanins are synthesized from tyrosine by a sequence of several reactions
• defect- albinism- affected individuals lack pigmentation since they cannot convert tyrosine to melanins

Question 9

Tryptophan as precursor

Answer 9

• precursor of serotonin, melatonin, and oxidized nicotinamide-adenine dinucleotide (NAD+)
• serotonin and melatonin are believed to promote better sleep, which has led to the use of supplements to try to boost levels
• a deficiency of Tryptophan can lead to niacin deficiency, which is called Pellagra. Pellagra is characterized by the four Ds, dermatitis, dementia, diarrhea, and death

Question 10

GABA

Answer 10

• GABA appears to be an inhibitory transmitter in the brain and spinal cord
• it is formed from L-glutamate by glutamate decarboxylase, a pyridoxal phosphate- dependent enzyme

Question 11

Histamine

Answer 11

• a potent vasodilator and may be a neural transmitter. It is released during allergic reactions. Antihistamine drugs are compounds that bear a structural similarity to histamine and can prevent the physiologic changes that is normally produces
• histidine decarboxylase catalyzes the formation of histamine from L-histidine

Question 12

Transfer of one-carbon groups

Answer 12

• occurs frequently in metabolism
• these one carbon fragments can be thought of as existing in a readily available pool with interchange between different oxidation states of carbon

Body needs single carbon fragments for:

1) Formation of methionine from homocysteine
2) Biosynthesis of purines
3) Biosynthesis of pyrimidines.
4) Biosynthesis of glycine from CO2 and NH4+ by glycine synthase

Question 13

Carriers for one carbon groups

Answer 13

• biotin- carrier of carbon dioxide, the most oxidized one carbon group. You saw this is glycolysis
• tetrahydrofolate-carrier one carbon groups of all oxidation states except carbon dioxide. THF can serve as an acceptor of one-carbon fragments in degradative reactions and as a donor of one carbon fragments in biosynthetic reactions

Question 14

Synthesis of tetrahydrofolate

Answer 14

• humans cannot synthesize the pterin ring, and the formation of tetrahydrofolate is dependent upon the dietary intake of a precursor, folate (pteroylglutamate, folic acid)
• folate in the diet is usually in the form of polyglutamines with the glutamate moieties attached in the y-peptidyl linkages, which are cleaved by conjugase, an enzyme in the intestinal mucosal cells
• this reaction leaves a single glutamate moiety on the absorbed vitamin
• the vitamin is usually in an oxidized state prior to absorption, and the intestinal mucosal cells also reduce the folic acid to tetrahydrofolic acid in two steps by dihydrofolic acid reductase
• folate is an essential B vitamin, that is destroyed in prepared foods. Rapidly dividing cells use a lot of folate
• bacteria make their own folate. Sulfa drugs inhibit the biosynthesis of folate by mimicking p-amino benzoic acid

Question 15

Oxidation and Reduction of folate

Answer 15

• Most reduced, -CH3, methyl, N5
• intermediate, -CH2-, methylene, N5 N10
• most oxidized, -CHO, formyl, N5
• CHNH, formino, N5
• CH=, methenyl, N5 N10

-formation of the N5-methyl form is non reversible in humans. It is only consumed by one reaction in the formation of methionine. More than 12% of the population is partially deficent in the enzyme that makes this form. These patients have a higher risk of heart disease and a lower risk of colon cancer

Question 16

Interconversion of Serine and Glycine

Answer 16

• Serine + THF Glycine or N5N10-methylene-THF
• glycine CO2 +NH4+ with NAD+ to NADH and H+

-since serine can be derived from 3-phosphoglyceric acid, there is a direct contribution to the 1-carbon pool from glycolysis

Question 17

Folate Deficiency

Answer 17

• since you need folate to make nucleotides it tends to affect rapidly dividing tissues
• the first symptoms are anemia

Question 18

Folate deficiency from drugs

Answer 18

• oral conctraceptives
• barbiturates: impairs absorption and utilization
• methotrexate: antimetabolite used in cancer chemotherapy

Question 19

Folate Defiency in Pregnancy

Answer 19

• partly due to demands of fetus
• in USA incidence of 50%. Usually in diets of prepared foods.
• leading cause of neural tube defects i.e. spina bifida
• spinal closure have dropped 10% since the initiation of folate supplementation of grain products

Question 20

Aminopterin and Methotrexate

Answer 20

• inhibit dihydrofolate reductase
• this leads to a deficiency of THF in rapidly dividing cells (tumors) that need THF for the synthesis of nucleotides
• in addition, bone marrow, hair follicles and gastrointestinal mucosa have limited amounts of THF and are also vulnerable
• all of these are rapidly dividing tissues

Question 21

S-Adenosylmethione

Answer 21

• is the major carrier of methyl groups to a wide variety of biomolecules
• some important methylation reactions involving methyl transfer from S-adenosylmethionine include:
  a) Norepinephrine to epinephrine
  b) Guanidinoacetate to creatine
  c) Acetylserotonin to melatonin
  d) Phosphatidylethanolamine to phosphatidylchole
  e) Methylation of DNA

Question 22

Methionine to S-adenosylmethionine

Answer 22

-in this reaction, the adenosyl group of adenosine triphosphate (ATP) is transferred to the methionine sulfur

Question 23

Methyl transfer from S-adenosylmethionine to an acceptor molecule

Answer 23

• the methyl group attached to the sulfur of S-adenosylmethionine is transferred to a nitrogen, oxygen or carbon atom of an acceptor molecule that yields the methylated product and S-adenosylhomocysteine
• S-adenosylhomocystein is hydrolyzed to adenosine and homocysteine

Question 24

Methyl transfer from S- adenosylmethionine

Answer 24

1) Methionine to S-adenosylmethionine
2) Methyl transfer from S-adenosylmethionine to an acceptor molecule
3) S-adenosylhomocysteine is hydrolyzed to adenosine and homocysteine
4) Regeneration of methionine from homocysteine
5) Alternatively cysteine is formed from homocysteine in two steps

Question 25

Regeneration of methionine from homocysteine

Answer 25

• this reaction is catalyzed by homocysteine methyltransferase
• the methyl group required to regenerate methionine is donated by N5-methyltetrahydrofolate, which is formed from N5,N10-methylenetetrahydrofolate by the enzyme N5N10-methylenetetrahydrofolate reducture
• homocysteine methyltransferase also uses as a cofactor vitamin B12. During the reaction the hydroxyl form of the cofactor is methylated to the methylcobalamin form. This then is the donor to homocysteine to form methionine

Question 26

Elevated homocysteine

Answer 26

• strongly correlated with increased risk of atherosclerosis
• vitamin supplementation with B12, folate and pyridoxal phosphate have been promoted as a means to reduce levels of homocysteine by helping to activate the enzymes that remove it

Question 27

Formation of cysteine from homocysteine

Answer 27

1-homocysteine and serine condense to form cystathionine

• catalyzed by cystathionine synthase
• cofactor pyridoxal phosphate
• disease- a deficiency of cystathionine synthase cause homocystinuria- children die by age 3-4 of heart disease or stroke

2- Cystathionine is hydrolyzed to form cysteine and alpha-ketobutyrate
enzyme- this reaction is catalyzed by cystathionase
disease- a deficiency in this enzyme causes cystathioninuria

Question 28

Other causes of homocystinuria

Answer 28

• inability to convert homocysteine to methionine because of a defect in homocysteine methyltranferae or a deficiency of tetrahydrofolate or methlcobalamin
• 1/8 in US have a deficiency of methylene-tetradhydrofolate reductase, causes more heart attacks but a lower incidence of colon cancer
• treatment: some patients have an enzyme deficient in binding pyridoxal phosphate. These forms of this disease may be treated with high doses of this vitamin

Question 29

Vitamin B12 (cobalamin)

Answer 29

• a coenzyme
• the central core of the molecule is a tetrapyrrole with a central cobalt atom bonded to 4 pyrrole nitogens
• the fifth bond is to a 5’-deoxyadenosine unit and the sixth bond is to dimethylbenzimidazole
• several forms of cobalamin in humans, they vary by the group attached to the fifth bond above the plain of the ring
• the adenosyl version is found in the MMAM reaction, while the hydroxy version is used in HMT reaction where it carries the methyl group in that position during the reaction
• most vitamin supplements have a CN group in that position

Question 30

Two reactions in human body that involve cobalamin

Answer 30

• conversion of L-methylmalonyl CoA to succinyl CoA

- the action of homocysteine methyltransferase

Question 31

Metabolic Diseases related to THF and Vitamin B12 deficiency

Answer 31

• deficiency of THF and B12 leads to megablastic anemia. Immature rbcs are released into the circulation, pernicious anemia
• B12 deficiency is associated with demyelination and degradation of the spinal cord. B12 deficiency is usually seen when there is a problem in the production of intrinsic factor, which carries B12 from the gut into the blood stream
• intrinsic factor important for absorption, made in stomach and absorbed in lower gut
• elderly people tend to make less intrinsic factor and some people develop an autoimmune disease that specifically destroys the instrinsic factor producing cells in the stomach
• B12 supplementation is often given by injection. Though less common there are also patients that are deficient in a specific protein that transports B12 around the body. This protein is called transcobalamine

Question 32

Folate Trap

Answer 32

• occurs when B12 is deficient, and causes a folate deficiency by trapping the folate in the N5 methyl form
• manifested as an anemia
• however, if folate is supplemented folate never becomes deficient and the B12 deficiency will cause neurological problems without the anemia
• because of the dangers of folate supplementation it began with grains only about 10 years ago