Eric Niederhoffer

SIU-SOM

What is the role of vitamins in metabolic pathways?

A 29-year-old woman is brought to the physician because of thought

abnormalities

A 38-year-old woman is brought to the physician because of frequent falls,

increasing confusion, and incontinence

Vitamins in Neuromuscular Metabolism

• Names and roles for vitamins and vitamin-like

substances

• Deficiencies and sources for vitamins and vitamin-

like substances

• Vitamin A transport

• Role in pathways (glycolysis, glycogenolysis, PPP)

• Role in pathways (TCA cycle, gluconeogenesis)

• Important neurologic amino acids

• Dopamine pathway

• Serotonin pathway

• Folate and B12 interrelationships

• Tetrahydrofolate conversions

• Tetrahydrofolate examples

• B12 examples

• Megaloblastic anemia

• Schilling test

Names and Roles for Vitamins and Vitamin-like Substances

Letter Name Role (metabolism)

A Retinol Phototransduction

B1 Thiamin Carbohydrate/myeline

B2 Riboflavin Redox/respiration

B3 Niacin Redox

B5 Pantothenic acid (CoA) TCA,FA,cholesterol

B6

PyridoxinePyridoxaminePyridoxal

AA, glycogenolysis

B7 Biotin Gluconeogenesis, TCA, FA, AA

B9 Folic acid 1C

B12 Cobalamin 1C&H

C Ascorbic acid Hydroxylation

p-Aminobenzoic acid Folate component

Choline AC, PL

Inositol PL

Lipoic acid TCA, acyl group transfer

Tetrahydrobiopterin (BH4) AAA hydroxylase, NO synthase

Deficiencies and Sources for Vitamins and Vitamin-like

SubstancesVitamin Deficiency Sources

A✱ Night blindness

Preformed: liver, egg yolk, butter, milkβ-carotene: dark green and yellow veggies

B1✱ Beri beriSeeds, nuts, wheatgerm, legumes, lean meat

B2Pellagra Meats, nuts, legumes

B3Pellegra Meats, nuts, legumes

B5Non known Yeast, grains, egg yolk, liver

B6Neurologic disease

Yeast, liver, wheatgerm, nuts, beans, banana

B7 Widespread injuryCorn, soy, egg yolk, liver, kidney, tomato

B9✱ Anemia Yeast, liver, leafy veggies

B12✱ Pernicious anemia Liver, kidney, egg, cheese

C✱ Scurvy Citrus and soft fruits

p-Aminobenzoic acid See B9 Liver rice bran, whole wheat

Choline RareWhole eggs, liver, beef steak, soy (lecithin)

Lipoic acid None known Liver

Inositol None known Cereal grains

Tetrahydrobiopterin (BH4) Rare, PKU-like Synthesized and recycled

Vitamin A Transport

RBPPA

β-carotene(plants)

retinal

retinol

retinyl ester(animals)

Liver storage

retinyl ester(small intestine)

retinol

Target tissue

PP avit B6

TKvit B1

Glycogenolysis

Glycogen

G1P

ALTvit B6Ala

R5PPPP

Role in Pathways(glycolysis, glycogenolysis, PPP)

G6PDH/6PGDHvit B3

Lactate

LDHvit B3

G3PDHvit B3

GlycolysisGlc

G6P

Pyr

G3P

1,3BPG

αKGDHvit B1,B2,B3, B5,

lipoic acid

PDHvit B1,B2,B3, B5, lipoic acid

ASTvit B6

Asp

Glu

Role in Pathways(TCA cycle, gluconeogenesis)

MDHvit B3

SDHvit B2

ICDHvit B3

PCvit B7

TCAcycle

αKG

SCoA

Acetyl-CoA

Pyr

OA

Suc

Mal

Fum

IC

ALTvit B6

BCKADHvit B1,B2,B3, B5,

lipoic acid

BCAAIle, Leu, Val

BCKA

DopamineNorepinephrineEpinephrine

Glutamate γ-Aminobutyrate

Serotonin

Tyrosine

Tryptophan

PLP (vit B6)

deCO2ase

PLP (vit B6)

deCO2ase

PLP (vit B6)

deCO2ase

Important Neurologic Amino acids

Phenylalanine

Phe OHaseBH4 Phenylketonuria (PKU)

Dopamine

Norepinephrine

TyrosinePLP (vit B6)

AAA deCO2aseDOPA

DβOHase Vit C, O2

Tyr OHase

BH4, O2

EpinephrinePNMT

SAMSAHC

Dopamine Pathway

Menkes disease

NormetanephrineMetanephrine

Vanillylmandelic acid (VMA)3-Methoxy-4-hydroxymandelic acid (HMMA)

Degradation (MAO/COMT)

Homovanillic acid(HVA)

Degradation

Serotonin(5-HT)Tryptophan

PLP (vit B6)

AAA deCO2ase5HTRP

Trp OHase

O2BH4,

Serotonin Pathway

5-Hydroxyindoleacetic acid(5-HIAA)

3-Hydroxykynurenine Xanthurenate

Cytosolic/mitochondrial degradation pathway

KynureninasePLP (vit B6)

Melatonin

Folate and B12 Interrelationships

Odd-numbered fatty acids

TCA cycleVit B12

Choline metabolism

Glycine

Methionine salvage

Met HCVit B12

RNA DNA

R5P HCO3-

Pyrimidine/Purinesynthesis

CTP UTPGTP ATP dGTP dATP

dCTP dTTP

N5-formimino-THFFolate

N5,N10-methylene-THF

Folate cycle

THF

DHF

N10-formyl-THF

N5,N10-methenyl-THF

N5-methyl-THF

Serine Histidine

Glutamate

Neurotransmitter metabolism

THF

Most reduced

Most oxidized

Tetrahydrofolate ConversionsFolate

DHF

DHF reductase

DHF reductase

(HC to Met)

N5-formimino-THF

(His to Glu)

(dUMP to dTMP to DNA)

(Ser to Gly) N10-formyl-THF

N5,N10-methenyl-THF

N5,N10-methylene-THF

N5-methyl-THF

THF N5-FTHF

Ser Glyserine hydroxymethyl

transferase

CO2 + NH4+

glycine synthase

THFN5,N10-MLTHF

PLPTHF

NAD+ NADH + H+

N5,N10-MLTHF

dUMP dTMPthymidylate synthase

N5,N10-MLTHF

7,8-DHF

Tetrahydrofolate examples

THF DHF reductaseA series of reductases

Choline DMG Sarcosine Gly

THFN5,N10-MLTHF THF

N5,N10-MLTHF

His Gluglutamate formimino transferase

FIGLU

B12 Examples

L-MMCoA SCoA

Met S-AdMet

S-AdHCHC

ATP +

Methyl transfers(1C metabolism)

Met synthase

Vit B12

TCAcycle

Odd-chainFA oxidation/

AA metabolismMMCoA mutase

Vit B12

(H exchange)

Met Ad transferase

A varietyof MTs

hydrolase

THF

N5MTHF

R

R-CH3

Purines, dTMP

Megaloblastic Anemia

http://library.med.utah.edu/WebPath/HEMEHTML/HEME083.html

This hypersegmented neutrophil is present along with macro-ovalocytes in a case of pernicious anemia. Compare the size of the RBC's to the lymphocyte at the lower left center. Such anemias can be due to B9 (folate) or to B12 (cobalamin) deficiency.

Schilling Test58Co-B12 + I.M. B12

58Co-B12-IF

IF present

GI absorption

Liver storage (~80%)

Plasma protein binding (~5%)

Excreted in urine (~15%)

58Co-B12

IF absent

No GI absorption

Fecal excretion

Low 58Co-B12 in urine

Stage Dose Normal Low1 Oral radioactive B12

I.M. unlabeled B12

8 to 40% of radioactive B12

in urine

malabsorption

2 ORB12/I.M.UB12/IF malabsorption unrelated to IF

3 ORB12/I.M.UB12/antibiotics

malabsorption unrelated to bacterial growth

4 ORB12/I.M.UB12/pancreatic enzymes

malabsorption unrelated to pancreatic insufficiency

Review Questions

• What are the different names for vitamins A, B1, B2, B3, B5, B6, C, and B12?

• Which pathway depends on vitamin A and how is it transported?

• Which pathways and enzymes depend on vitamin B1, B2, B3, B6, B9, and B12?

• Which pathway and enzyme depends on p-aminobenzoic acid, choline, lipoic acid, and tetrahydrobiopterin?

• What are some clinical features and tests of vitamin deficiencies?