19 - Folatemediated1carbonmetabolism andpurinesynthesis...

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Folate mediated 1 carbon metabolism and purine synthesis arch 23 2011 March 23, 2011 manda MacFarlane PhD Amanda MacFarlane, PhD Health Canada
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NA synthesis DNA synthesis hy is it important? Why is it important? What happens when things go wrong?
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verview of Lecture 1 Overview of Lecture 1 ll roads lead to….purine synthesis All roads lead to….purine synthesis Folate metabolism–WHY? Pentose phosphate pathway – WHAT? Formation of the purine ring–HOW? FOCUS ON: Regulatory steps: Key enzymes/substrates/products athway flux ed forward and negative back Pathway flux – feed forward and negative back Concepts of compartmentalization, substrate channeling, enzyme interactions
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late Folate ater soluble B vitamin Water soluble B vitamin Synthetic form is folic acid One carbon metabolism Carries and activates one carbon groups Required for de novo synthesis of purines and thymidylate, as well as methionine synthesis
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onversion of folate to THF Conversion of folate to THF FOLIC ACID *THF carries all of those 1Cs*
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Oxidation levels of C1 groups carried by THF Oxidation level Group carried THF derivative Formate Formyl ( CH=O) Formimino ( CH=NH) N 5 Formyl THF, N 10 Formyl THF N 5 Formimino THF ( ) Methenyl ( CH=) N 5 ,N 10 Methenyl THF Formaldehyde Methylene ( CH 2 )N 5 10 Methylene THF ethanol ethyl ( H 5 ethyl HF Methanol Methyl ( CH 3 ) N Methyl THF Formate comes from the mitochonodria
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Folate-mediated one-carbon metabolism DHF Folic acid (Folate) Cytoplasm MacFarlane A J et al. J. Biol. Chem. 2009;284:1533-1539 ©2009 by American Society for Biochemistry and Molecular Biology
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De novo purine synthesis
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Purine ring structure derived from many molecules N1 = ASPARTATE C2 +C8 = FORMATE N3 + N9 = AMIDE GROUP FROM GLUTAMINE C4, C5 + N7 = GLYCINE 6 = HC0 - C6 C0 3 IMP = nucleotide of the base hypoxanthine
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. Activation of ribose ‐ ‐ hosphate 1. Activation of ribose 5 phosphate roduct of pentose phosphate pathway Product of pentose phosphate pathway Pyrophosphoryl group transferred directly om ATP to R5P C1 H group from ATP to R5P C1 OH group PRPP is common to purine and pyrimidine synthesis *This means GO* Negatively regulated
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2 5 4 3 1 7 6
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This note was uploaded on 12/18/2011 for the course BCH 3120 taught by Professor Mary-ellenharper during the Winter '11 term at University of Ottawa.

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19 - Folatemediated1carbonmetabolism andpurinesynthesis...

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