Transcript Vitamins in Neuromuscular Metabolism

A 38-year-old woman is brought to the
physician because of frequent falls,
increasing confusion, and incontinence
A 29-year-old woman is brought to the
physician because of thought
abnormalities
What is the role of vitamins in metabolic
pathways?
Eric Niederhoffer
SIU-SOM
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
Pyridoxine
Pyridoxamine
Pyridoxal
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 Substances
Vitamin
Deficiency
Sources
A✱
Night blindness
Preformed: liver, egg yolk, butter,
milk
β-carotene: dark green and
yellow veggies
B1✱
Beri beri
Seeds, nuts, wheatgerm,
legumes, lean meat
B2
Pellagra
Meats, nuts, legumes
B3
Pellegra
Meats, nuts, legumes
B5
Non known
Yeast, grains, egg yolk, liver
B6
Neurologic
disease
Yeast, liver, wheatgerm, nuts,
beans, banana
B7
Widespread injury
Corn, 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
Rare
Whole 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
β-carotene
retinyl ester
(plants)
(animals)
retinal
retinol
retinyl ester
(small intestine)
Liver storage
PA RBP retinol
Target tissue
Role in Pathways
(glycolysis, glycogenolysis, PPP)
Glycogenolysis
Glc
Glycolysis
Glycogen
PP a
vit B6
G1P
G6P
G6PDH/6PGDH
vit B3
R5P
PPP
TK
vit B1
G3P
G3PDH
vit B3
1,3BPG
Ala
ALT
vit B6
Pyr
LDH
vit B3
Lactate
Role in Pathways
(TCA cycle, gluconeogenesis)
Pyr
PDH
vit B1,B2,B3, B5, lipoic acid
Acetyl-CoA
PC
vit B7
AST
vit B6
Asp
MDH
vit B3
BCAA
Ile, Leu, Val
OA
TCA
cycle
Mal
IC
ICDH
vit B3
Fum
BCKA
SDH
vit B2
αKG
Suc
SCoA
BCKADH
vit B1,B2,B3, B5,
lipoic acid
ALT
vit B6
αKGDH
vit B1,B2,B3, B5,
lipoic acid
Glu
Important Neurologic Amino acids
Glutamate
PLP (vit B6)
γ-Aminobutyrate
deCO2ase
Phenylalanine
BH4
Phe OHase
Tyrosine
Phenylketonuria (PKU)
PLP (vit B6)
deCO2ase
Tryptophan
PLP (vit B6)
deCO2ase
Dopamine
Norepinephrine
Epinephrine
Serotonin
Dopamine Pathway
Homovanillic acid
(HVA)
Degradation
Tyrosine
BH4, O2
PLP (vit B6)
DOPA
Tyr OHase
Dopamine
AAA deCO2ase
Menkes disease
PNMT
Epinephrine
DβOHase
Vit C, O2
Norepinephrine
SAHC SAM
Metanephrine
Normetanephrine
Degradation (MAO/COMT)
Vanillylmandelic acid (VMA)
3-Methoxy-4-hydroxymandelic acid (HMMA)
Serotonin Pathway
Melatonin
PLP (vit B6)
Serotonin
Tryptophan
5HTRP
Trp OHase
AAA deCO ase (5-HT)
BH4, O2
2
5-Hydroxyindoleacetic acid
(5-HIAA)
3-Hydroxykynurenine
PLP (vit B6) Kynureninase
Cytosolic/mitochondrial
degradation pathway
Xanthurenate
Folate and B12 Interrelationships
Folate
Folate cycle
N5-formimino-THF
DHF
THF
N10-formyl-THF
N5,N10-methenyl-THF
Pyrimidine/Purine
synthesis
R5P
HCO3-
GTP ATP
CTP UTP
dGTP dATP
dCTP dTTP
RNA
DNA
N5,N10-methylene-THF
N5-methyl-THF
Methionine
salvage
Met
Vit B12
HC
Odd-numbered
TCA cycle
fatty acids Vit B
12
Choline
metabolism
Neurotransmitter
metabolism
Serine
Histidine
Glycine
Glutamate
Tetrahydrofolate Conversions
Folate
DHF
reductase
(dUMP to dTMP
to DNA)
DHF
DHF
reductase
THF
Most
oxidized
(Ser to
Gly)
(HC to Met)
(His to
Glu)
N10-formyl-THF
N5-formimino-THF
N5,N10-methenyl-THF
N5,N10-methylene-THF
N5-methyl-THF
Most
reduced
Tetrahydrofolate examples
N5,N10THF MLTHF
Choline
DMG
Sarcosine
NAD+
THF
PLP
N5,N10MLTHF THF
Ser
N5,N10THF MLTHF
NADH + H+
N5,N10MLTHF
CO2 + NH4+
Gly
serine hydroxymethyl
transferase
glycine synthase
N5-FTHF
THF
FIGLU
His
Gly
Glu
glutamate formimino transferase
dUMP
dTMP
N5,N10MLTHF
7,8-DHF
thymidylate synthase
A series of reductases
THF
DHF reductase
B12 Examples
Odd-chain
FA oxidation/
AA metabolism
MMCoA mutase
L-MMCoA
SCoA
Vit B12
(H exchange)
TCA
cycle
Methyl transfers
(1C metabolism)
Met Ad transferase
ATP + Met
S-AdMet
THF
R
Met synthase
Vit B12
N5MTHF
A variety
of MTs
R-CH3
hydrolase
HC
Purines, dTMP
S-AdHC
Megaloblastic Anemia
This hypersegmented neutrophil is present along with macroovalocytes 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.
http://library.med.utah.edu/WebPath/HEMEHTML/HEME083.html
Schilling Test
58Co-B
12
+ I.M. B12
IF present
IF absent
58Co-B -IF
12
58Co-B
12
GI absorption
No GI absorption
Liver storage
(~80%)
Plasma protein
binding (~5%)
Low 58Co-B12
in urine
Excreted in urine
(~15%)
Stage
Dose
1
Oral radioactive B12
I.M. unlabeled B12
2
ORB12/I.M.UB12/IF
3
ORB12/I.M.UB12/antibi
otics
4
ORB12/I.M.UB12/pancr
eatic enzymes
Fecal excretion
Normal
Low
malabsorption
8 to 40% of
radioactive B12
in urine
malabsorption unrelated
to IF
malabsorption unrelated
to bacterial growth
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?