Role of B6 phosphate in amino acid metabolism

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Presented By: RAMESSUR: KAVISH S.A.(ROLL NUMBER: 95)

VITAMIN B-6 CHEMISTRY, ACTIVATION AND ROLE IN AMINO ACID METABOLISM

Introduction to Vitamin B6

Structure of Vitamin B6

Activation of Vitamin B6

Role in Amino Acid Metabolism

Overview of Seminar

General Amino Acid Reactions

Metabolism of Tryptophan

Metabolism of Methionine

Metabolism of Glycine

Introduction to Vitamin B6




Overview of Seminar





B-Complex Vitamins

Water Soluble Vitamins Earlier thought of as being a Single Vitamin Later found to be composed of EIGHT Chemically distinct Vitamins

Vitamin B1 (Thiamine)

Vitamin B2 (Riboflavin)

Vitamin B3 (Niacin)

Vitamin B5

(Pantothenic Acid)

Vitamin B6

Vitamin B7 (Biotin)

Vitamin B9 (Folic Acid)

Vitamin B12 (Cobalamin)

INTRODUCTION:

B-Complex Vitamins

Water Soluble Vitamins Earlier thought of as being a Single Vitamin Later found to be composed of EIGHT Chemically distinct Vitamins



Vitamin B3 (Niacin)

Vitamin B5

(Pantothenic Acid)

Vitamin B6

Vitamin B7 (Biotin)



Vitamin B6

INTRODUCTION:

B-Complex Vitamins

INTRODUCTION: Water Soluble Vitamins

Earlier thought of as being a Single Vitamin Later found to be composed of EIGHT Chemically distinct Vitamins



Vitamin B3 (Niacin)

Vitamin B5

(Pantothenic Acid)

Vitamin B6

Vitamin B7 (Biotin)



Vitamin B6

HISTORY:

Introduction

Discovered in 1934 Hungarian physician, Paul György Ability to cure Dermititis Acrodynia in Rats

Isolated in 1938 Polish nutritionist, Samuel Lepkovsky Isolated from Rice Bran

Structure of Pyridoxine in 1939 Harris and Folkers

Structure of Pyridoxal and Pyridoxamine in 1945 American Biochemist, Esmond Snell

GOOD SOURCES

Sources of Vitamin B6

Vitamin B6 is ABUNDANTLY present in: Royal Jelly of Bees Yeast Rice Polishing Cereal Grains Egg Yolk Germinal portion of various Seeds

MODERATE SOURCES

Vitamin B6 is MODERATELY present in: Liver Kidney Muscle Fish

POOR SOURCES

Vitamin B6 is POORLY present in: Milk

Structure Derivatives of Purine Ring

Purine Ring


Purine RingPyridoxine

2-Methly, 3-Hydroxy, 4,5-diHydroxyMethly Pyridine

Pyridoxine

Structure

Pyridoxal

Purine RingPyridoxal

Structure

Pyridoxamine

Purine RingPyridoxamine


Pyridoxine Also known as Pyridoxol 4th position contains a CH2OH group Precursor from of Vitamin B6

Plant in origin Pyridoxine

Pyridoxal

Pyridoxamine

Pyridoxal 4th position contains a CHO group Precursor from of Vitamin B6

Plant in origin

Pyridoxamine 4th position contains a CH2NH2 group Precursor from of Vitamin B6

Plant in origin

Structure

Biochemically active only when Phosphorylated Phosphorylation is brought about by Kinase enzyme Phosphorylation occurs at 5th Position

Pyridoxine Pyridoxine-P (Phosphate)

Kinase

Structure

Pyridoxine Also known as Pyridoxol 4th position contains a CH2OH group Precursor from of Vitamin B6

Plant in origin

Pyridoxal 4th position contains a CHO group Precursor from of Vitamin B6

Plant in origin

Pyridoxamine 4th position contains a CH2NH2 group Precursor from of Vitamin B6

Plant in origin

Pyridoxine

Pyridoxal

Pyridoxamine

Structure

Pyridoxine

Pyridoxal

Pyridoxamine

Pyridoxine-P

Pyridoxal-P

Pyridoxamine-P

Kinase

Kinase

Kinase

Structure

Biochemically active only when Phosphorylated Phosphorylation is brought about by Kinase enzyme Phosphorylation occurs at 5th Position In total, there are 6 isoforms of Vitamin B6:

Pyridoxine Pyridoxine-P (Phosphate)

Pyridoxine Pyridoxine-P Pyridoxal Pyridoxal-P Pyridoxamine Pyridoxamine-P

Structure



Pyridoxic Acid Excretory form of Vitamin B6

Oxidation at 4th position

Pyridoxic Acid

NOTE: Vitamin B6 can also be excreted in the UNCHARGED form as Pyridoxine or Pyridoxal

Structure



Pyridoxic Acid Excretory form of Vitamin B6

Oxidation at 4th position

Pyridoxic Acid

NOTE: Vitamin B6 can also be excreted in the UNCHARGED form as Pyridoxine or Pyridoxal


Biologically active forms are: a) Pyridoxal-PO4

b) Pyridoxamine-PO4

Pyridoxine Pyridoxal

Pyridoxal-P

Dehydrogenase

Pyridoxal Kinase

H2 ATP

ADP

Zn2+

Mg2+


Absorption is by either PASSIVE or ACTIVE mechanisms Vitamin B6 is absorbed by ACTIVE TRANSPORT

Amino Acid Absorption



Transamination Reactions SGPT (Serum Glutamate Pyruvate Transaminase)

Glutamate Pyruvate




Glutamate Pyruvate




Glutamate PyruvateAlanine α-keto Glutarate


Pyridoxal-P

Pyruvic Acid (Recipient α-keto acid)

Glutamate(Donor α-amino acid)

Mechanism of Reaction


Pyridoxal-P




Pyridoxal-P



Pyridoxal-P



α-keto Glutarate(New α-keto acid) Pyridoxamine-P




Pyridoxal-P



α-keto Glutarate(New α-keto acid) Pyridoxamine-P

Alanine (New α-amino acid)

Pyridoxal-P





α-keto Glutarate(New α-keto acid)

Alanine(New α-amino acid)

Pyruvate(Recipient α-keto acid)


SGPT

B6-P+ +




α-keto Glutarate(New α-keto acid)

Alanine(New α-amino acid)

Pyruvate(Recipient α-keto acid)


SGPT

B6-P+ +




Pyruvate + Glutamate Alanine + α-keto Glutarate

SGOT (Serum Glutamate Oxaloacetate Transaminase)

Oxaloacetate + Glutamate Aspartate + α-keto Glutarate

CLINICAL SIGNIFICANCE

Synthesis of Non-Essential Amino Acids Alanine Aspartate

Recycling of Carbon Skeletons Pyruvate Oxaloacetate




Pyruvate + Glutamate Alanine + α-keto Glutarate

SGOT (Serum Glutamate Oxaloacetate Transaminase)

Oxaloacetate + Glutamate Aspartate + α-keto Glutarate


Synthesis of Non-Essential Amino Acids Alanine Aspartate

Recycling of Carbon Skeletons Pyruvate Oxaloacetate



Deamination Reactions Non-Oxidative Deamination

Serine




Dehydrase

H2O

B6-P

H2ONH3

Serine Imino Acid

Pyruvate

Imino Acid




Dehydrase

H2O

B6-P

H2ONH3

Serine Imino Acid

Pyruvate

Imino Acid




Serine Deamination

Cysteine DeaminationSerine

Cysteine

Pyruvate

Pyruvate

Water

Hydrogen Sulphide

+

+

Dehydrase

B6-P

Desulfhydrase

B6-P

CLINICAL SIGNIFICANCE Breakdown of excess amino acids in Liver Contributes to NH3 formation in the body

NH3

NH3




Serine Deamination

Cysteine DeaminationSerine

Cysteine

Pyruvate

Pyruvate

Water

Hydrogen Sulphide

+

+

Dehydrase

B6-P

Desulfhydrase

B6-P

CLINICAL SIGNIFICANCE Breakdown of excess amino acids in Liver Contributes to NH3 formation in the body

NH3

NH3



Interconversion of Amino Acids

Racemases Conversion of L-amino Acids to D-Amino Acids Conversion of D-Amino Acids to L-Amino Acids

RACEMASE

B6-P

L-AlanineD-Alanine



Interconversion of Amino Acids

Racemases Conversion of L-amino Acids to D-Amino Acids Conversion of D-Amino Acids to L-Amino Acids

RACEMASE

B6-P

L-AlanineD-Alanine



Decarboxylation Reactions Removal of CO2 to produce AMINES

Histidine




Decarboxylase

B6-P

CO2

Histidine




Decarboxylase

B6-P

CO2

HistamineHistidine




Decarboxylase

B6-P

CO2

HistamineHistidine




Histidine

5-OH Tryptophan

Glutamic Acid

Histamine

5-OH Tryptamine (Serotonin)

γ-Amino Butyric Acid

DecarboxylaseB6-P

CO2

DecarboxylaseB6-P

CO2

DecarboxylaseB6-P

CO2

Histamine Synthesised by Basophils and Mast Cells Mediator of Hypersensitivity Reactions Triggers Inflammatory Reactions Neurotransmitter in the Gut

γ-Amino Butyric Acid

Inhibitor Neurotransmitter in the CNS GABA Deficiency produces a state of Hyper excitation Convulsions Precipitating factor for Epileptic Seizures

Serotonin Neurotransmitter in CNS Regulates Behaviour and Cognitive functions Deficiency leads to Depression, Anxiety and Personality Disorders Regulates Intestinal Motility in Gut




Tryptophan Metabolism

Tryptophan

Kynurenine

3-OH-Kynurenine

3-OH-Anthranilic Acid

NIACIN

Kynureninase

B6-P



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P

CLINICAL SIGNIFICANCE Pathway for Endogenous NIACIN synthesis

In Vitamin B6 deficiency Niacin Deficiency PELLAGRA sets in

† Dermatitis



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P



† Dermatitis



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P



† Dermatitis† Dementia



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P



† Dermatitis† Dementia† Diarrhoea



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P



† Dermatitis† Dementia† Diarrhoea† DEATH



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P




In ISONIAZID therapy for TuberculosisIsoniazid

+

Isoniazid B6-P Hydrasone

B6-P



Tryptophan

Kynurenine

3-OH-Kynurenine


NIACIN

Kynureninase

B6-P




In ISONIAZID therapy for TuberculosisIsoniazid

+

Isoniazid B6-P Hydrasone

B6-P

B6-P



Tryptophan

NIACIN


In Vitamin B6 deficiency In ISONIAZID therapy for Tuberculosis

Tryptophan Loading TestKynurenine

3-OH-Kynurenine


Kynureninase

B6-P

Kynurenine

3-OH-Kynurenine


Kynureninase

B6-P



Tryptophan

NIACIN




3-OH-Kynurenine


Kynureninase

B6-P

Kynurenine

3-OH-Kynurenine


Kynureninase

B6-P

Kynurenine

3-OH-Kynurenine


Kynureninase

B6-PXanthurenic Acid



Tryptophan

NIACIN




3-OH-Kynurenine


Kynureninase

B6-P

Kynurenine

3-OH-Kynurenine


Kynureninase

B6-P

Kynurenine

3-OH-Kynurenine


Kynureninase

B6-PXanthurenic Acid


Methionine Metabolism Methionine metabolism occurs in 2 phases

Phase I - Conversion of Methionine to HOMOCYSTEINE Phase II - Further metabolism of HOMOCYSTEINE

Methionine

HOMOCYSTEINE Serine+

Cystathionine

CysteineHomoserine

Cystathionine β SynthaseB6-P

Cystathionine LyaseB6-P

CLINICAL SIGNIFICANCE Pathway for synthesis of Non-Essential Amino Acids like Cysteine In Vitamin B6 deficiency

HOMOCYSTEINAEMIA Homocysteine is Atherogenic Ischaemic Heart Disease Brain Stroke


Glycine Metabolism

Glycine

HydroxyMethly THF

Interconversion of Glycine to Serine

Serine Hydroxymethly Transferase

B6-P

Glycine

Serine

“Free” THF

HydroxyMethly THF


Glycine Metabolism


CLINICAL SIGNIFICANCE Synthesis of Non-Essential

Amino Acid Serine

Serine Hydroxymethly Transferase

B6-P

Glycine

Serine

“Free” THF

HydroxyMethly THF


Glycine Metabolism


CLINICAL SIGNIFICANCE Synthesis of Non-Essential

Amino Acid Serine

Tetra Hydro Folate

B6-P

GCSGlycine


Glycine Metabolism

Glycine Cleavage System

Tetra Hydro Folate

+

N5,10 Methylene Tetra Hydro Folate

B6-P

GCSGlycine


Glycine Metabolism


Carbon Dioxide Ammonia

+B6-P

GCSGlycine


Glycine Metabolism



dUMP dTMP

Di Hydro Folate

DNA SynthesisN5,10 Methylene Tetra Hydro Folate

Thymidylate Synthase


+B6-P

GCSGlycine


Glycine Metabolism



dUMP dTMP

Di Hydro Folate

DNA Synthesis

Thymidylate Synthase


N5,10 Methylene Tetra Hydro Folate

GlycineAcetyl CoA

+


Glycine Metabolism

Synthesis of Amino Acetone

GlycineAcetyl CoA

Amino Acetone Synthetase

B6-P

+


Glycine Metabolism


Amino Acetone

GlycineAcetyl CoA

Amino Acetone Synthetase

B6-P

+


Glycine Metabolism



Amino Acetone has a role in Metabolism†† Elliott, W.H., et al., 1959. Amino Acteone: Its Isolation and Role in Metabolism, Canberra. Nature: 183, 1051-1052.

Sources of Vitamin B6



Role in Amino Acid Metabolism General Amino Acid Reactions




SUMMARY

+ RELEVANT CLINICAL SIGNIFICANCES

TEXTBOOKS

Biehl, J.P., et al., 1954. Effect of Isoniazid on Vitamin B6 Metabolism; Its Possible Significance in Producing Isoniazid Neuritis, London. Royal Society of Medicine Press; 85:389-392.

Robinson, K., et al., 1996. Hyperhomocysteinemia Confers an Independent Increased Risk of Atherosclerosis in End-Stage Renal Disease and Is Closely Linked to Plasma Folate and Pyridoxine Concentrations, Boston. Circulation; 94:2743-2748

Bibliography

Chatterjea, M.N., Shinde, R., 2008. Textbook of Medical Biochemistry, 7th Edition, New Delhi. Jaypee.

Murray, R.K., et al., 2009. Harper’s Illustrated Biochemistry, 28th Edition, New York. McGraw Hill.

Champe, C., et al., 2008. Lippincott’s Illustrated Review of Biochemistry, 4th Edition , New York. Lippincott Williams and Wilkins.

SCIENTIFIC PAPERS

LECTURE NOTES Chabba, N., 2011. Vitamin B6 chemistry, Activation and Role in Amino Acid

Metabolism. Biochemistry Lecture, Mauritius, SSR Medical College. UNPUBLISHED.

THANK YOU

Education

Role of B6 phosphate in amino acid metabolism