Transcript WHAT ARE NEURAL TUBE DEFECTS (NTDs)?

Folic Acid
FIGURE 1: Chemical Structure of Folic Acid [8]
By:
Linda Kim
Andrew Liu
Milton Reisis
PHM 226, Example
Instructor: Dr. Jeffrey Henderson
WHAT IS FOLIC ACID?
Folic acid = pteroylmonoglutamic acid, folacin,
vitamin Bc, vitamin B9 and Lactobacillus casei
factor [8].
Folic acid is a water-soluble B-vitamin [8]
MW = 441kDa
Must be ingested in diet (cannot be synthesized
by body)
WHY IS FOLIC ACID NEEDED?
Formation of the coenzyme referred to as
tetrahydrofolate (THF) [1]
Essential for creating heme, the iron containing
substance in haemoglobin [1]
Proper formation of the brain, spinal cord, and
nerve cells in the embryo. Closure of the neural
tube in the fetus cannot be completed without it
(Northrup H, 2000).
Essential for synthesis of serine, methionine,
ATP, GTP, thymidylate
ABSORPTION
Natural food source (polyglutamate): conjugase
in the small intestine’s lumen converts
polyglutamates (low absorption) to
monoglutamates for absorption [4]
Monoglutamate is readily absorbed from the gut
via energy-dependent, carrier-mediated
mechanisms, involving membrane-associated
folate-binding proteins [4]
DISTRIBUTION
Tetrahydrofolate (THF) and its derivatives
distribute to all body tissues [4]
N5-methyl-THF is the major storage form
of folate in the body (i.e. ~50% in liver) [4]
N5-methyl-THF is highly bound to albumin
[4]
METABOLISM
Folate reduced to dihydrofolate (DHF) and then to tetrahydrofolate
(THF) within cells, by dihydrofolate reductase (DHFR) and NADH [7]
Addition of glutamate residues to THF in the cell keep it within the
cell to form its active coenzyme in one-carbon metabolism reactions
[7]
5-methyl-THF is formed by the reduction of N5, N10-methylene-FH4
by N5, N10-methylene-THF reductase [7]
Normally, folate is excreted in the urine; folate is also excreted in the
bile, if not reabsorbed [4]
TABLE 1: One-carbon pool: Sources and Recipients of
Carbon [7]
Source
Form of THF
produced
Recipient
Product
Formate
N10-Formyl
Purine precursor
Purine (C2)
Histidine
N5, N10-Methenyl
Purine precursor
Purine (C8)
Serine, Glycine,
Formaldehyde
N5, N10-Methylene
dUMP
Glycine
dTMP
Serine
Reduction of N5,
N10-methyleneTHF
N5-Methyl
Vitamin-B12
Methyl-B12
HOW DOES FOLIC ACID WORK?
Folic acid is converted to its active
coenzyme form, THF, which behaves as a
donor or receiver of a one carbon entity in
different oxidation states (formyl,
methylene, or methyl)
FIGURE 2: FOLATE MECHANISM OF ACTION [9]
FIGURE 3: MECHANISM OF ACTION – EXAMPLE [9]
FIGURE 4: MECHANISM OF ACTION – EXAMPLE [2]
Sources of Folic Acid
Cereals (100-400 mcg), dark green
vegetables (120-160 mcg), citrus fruits
(50-100 mcg) [10]
Folic acid may also be found in
supplements and multivitamin
combinations sold at pharmacies
Folate Deficiency
Causes of Folate Deficiency
Decreased intake (diet, malabsorption)
Increased need (pregnancy)
Also, consider decreased availability
(antifolate drugs etc.)
WHAT ARE NEURAL TUBE
DEFECTS (NTDs)?
The neural tube forms in the embryo
and then closes (between the 2nd and 4th
week of gestation)
A neural tube defect occurs when the
neural tube fails to close properly
The two most common NTDs are
anencephaly and spina bifida
What is Spina Bifida?
Occurs when the two sides of the spine fail to
close and protect the spinal cord
There are two forms of spina bifida:
1) Spina bifida occulta (mildest form)
2) Spina bifida manifesta which includes two types of
spina bifida: meningocele and myelomeningocele
What is Spina Bifida?
Source: http://www.surgical-tutor.org.uk/default-home.htm?system/hnep/neural_tube.htm~right
What Causes Spina Bifida?
Largely unknown
Some evidence suggests that genes may
be involved. (Northrup H et al, 2000)
A high fever during pregnancy or epileptic
women who have taken the drug valproic
acid to control seizures may have an
increased risk of having a baby with spina
bifida. (Lewis DP et al, 1998)
How Can NTDs be Prevented?
All women of childbearing age should receive 0.4
mg (400 micrograms) of folic acid daily prior to
conception of planned or unplanned pregnancies
and continue thru 1st trimester
Women with a history of NTD and should receive
daily supplementation of 4 mg (4000 micrograms)
of folic acid starting three months prior to
conception and continuing thru the 1st trimester
References
[1] Adams, S.L. 2003. Biochemical Functions of Folic Acid, http://www.i2k.com/~suzanne/page25.htm, accessed
January 2004.
[2] Angstadt, C.N. 1997. Purine and Pyrimidine Metabolism,
http://www.mcphu.edu/netbiochem/pupyr/pp.htm#Syn%20TMP, accessed January 2004.
[3] Castillo, E.S. 1991. Folic Acid,
http://www.inchem.org/documents/pims/pharm/folicaci.htm#PartTitle:3.%20PHYSICOCHEMICAL%20PROPERTIES, accessed January 2004.
[4] Expert Group on Vitamins and Minerals. 2002. Review of Folic Acid,
http://www.foodstandards.gov.uk/multimedia/pdfs/evm0018p.pdf, accessed January 2004.
[5] Fenech M. 2001. The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475(1-2):5767
[6] Larsen, H.R. 2000. Folic Acid: Don’t Be Without It!, http://vvv.com/healthnews/folic_acid.html, accessed January
2004.
[7] Marks, D.B., Marks, A.D., and Smith, C.M. 1996. Basic Medical Biochemistry: A Clinical Approach., Williams and
Wilkins, Maryland, pp 613-632.
[8] No author. 2002. Folic Acid, http://www.chm.bris.ac.uk/webprojects2002/schnepp/folic.html, accessed January
2004.
[9] No author. 2002. Main Folate Metabolism Pathways,
http://www.humboldt.edu/~rap1/BiochSupp/PathwayDiagrams/FolMetPath.gif, accessed January 2004.
[10] No author. 2003. CERHR: Folic Acid, http://cerhr.niehs.nih.gov/genpub/topics/folic_acid-ccae.html, accessed
January 2004.
[11] Wolfson, D. 2001. Pharmaceutical Drugs Deplete Folic Acid,
http://www.newhope.com/nutritionsciencenews/NSN_backs/Sep_01/folic.cfm, accessed January 2004.
References
*For NTD section
AllRefer Health – Caring for your Well Being: http://health.allrefer.com/health/folic-acid-folate-info.html
Champel V et al. Should folic acid be given to women treated with valproic acid and/or carbamazepine? Folic acid
and pregnancy in epilepsy. Rev Neurol. 1999 Mar; 155(3): 220-4.
Geisel J. Folic acid and neural tube defects in pregnancy: a review. J Perinat Neonatal Nurs. 2003 Oct-Nov; 17(4):
268-79.
Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic
drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998 Jul-Aug; 32(7-8): 802-17.
Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part II:
Improvement with folic acid. Ann Pharmacother. 1998 Sep; 32(9): 947-61. Review.
MEDLINEplus – Spina Bifida: http://www.nlm.nih.gov/medlineplus/spinabifida.html
MEDLINEplus – Folic Acid: http://www.nlm.nih.gov/medlineplus/folicacid.html
Northrup H et al. Spina bifida and other neural tube defects. Curr Probl Pediatr. 2000 Nov-Dec; 30(10): 313-32.
Pregnancy and Nutrition - Spina Bifida and Folic Acid: http://www.bchealthguide.org/healthfiles/hfile38c.stm
Ray JG et al. Association of neural tube defects and folic acid food fortification in Canada. Lancet. 2002 Dec 21-28;
360(9350): 2047-8.
Spina Bifida Association of America – Facts about Spina Bifida: http://www.sbaa.org/html/sbaa_facts.html
Surgical-tutor.org.uk – a free online surgical resource: http://www.surgical-tutor.org.uk/defaulthome.htm?system/hnep/neural_tube.htm~right
The Arc – Prevention of Neural Tube Defects: http://www.thearc.org/faqs/folicqa.html
Wald NJ. Folic Acid and the Prevention of Neural-Tube Defects.N Engl J Med. 2004 Jan 8; 350(2): 101-3.
References
*For anemia section
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Folic Acid. USP DI Vol. 1 Drug Information for the Health Care Professional. 23rd Ed. Micromedex: Colorado,
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