NITROGEN BIOSYNTHETIC PATHWAYS

BIOC 460 DR. TISCHLER LECTURE 39

OBJECTIVES

1. Outline the pathways for synthesis of the following nonessential amino acids by identifying the primary source of the carbons and the nitrogen for their synthesis (alan, arg, asp, glu, gln, and tyr) in humans.

1. General role of cofactors-derived from folic acid and how these are important in metabolism of ser, gly, met and cys

1. Discuss significance of S-adenosylmethionine in "one-carbon" metabolism

4. Identify two specific cofactor forms of vitamin B12 and list the amino acids whose metabolism depends on each form.

5. Concerning heme synthesis:a) describe the reactions involved in the formation of

porphobilinogenb) discuss the key features of its regulation c) explain why lead poisoning would affect the oxygen

carrying ability of the blood.

6. List the steps in the catabolism of heme to conjugated bilirubin and identify the general condition associated with the accumulation of bilirubin in the body.

OBJECTIVES (cont.)

ornithine

pyruvate

-ketoglutarate

glutamate

alanineA

+aspartate

arginino-succinate arginine

B

phenylalanine

tyrosine

F

glutamate

citrulline

+ carbamoyl phosphate

NH3 + CO2 + ATP

oxaloacetate

aspartateC

-ketoglutarate

glutamate

ADP + Pi

NH3 + ATP

glutamine

E

glutamate

-ketoglutarate+ NH3

NAD(P)H

NAD(P)+

D

glutamate

Figure 1. Synthesis of the nonessential amino acids alanine (A), arginine (B), aspartate (C), glutamate (D), glutamine (E), and tyrosine (F).

Figure 2. Synthesis of the nonessential amino acids asparagine, serine, glycine. CH2-THF is methylene tetrahydrofolate

aspartate asparagine

glutamine glutamate

glycineserine

THF CH2-THF

3-phosphoglycerate

NAD+ + glutamate + H2O NADH + -ketoglutarate + Pi

serine

CH2-THF+ NADH

THF+ NAD+

NH3 + CO2 glycine

glycine synthase

Methionine-CH3

Homocysteine

CH3 group donation

adenosine

S-Adenosylmethionine

ATP

Figure 3. Metabolism of CH3-THF, CH3-Cbl, met and cys.

CH3

Cysteine Cystathionine

N5-CH3 THF

THF

Hydroxy B12

CH3-B12

Methionine synthase

CH3

CH3

CH3

CH3

Table 1. Summary of the roles of folate and cobalamin in nitrogen metabolism

Cofactor Vitamin precursor

Role

Methyl-cobalaminCobalamin (vitamin B12)

methionine metabolism

Adenosyl-cobalamin isoleucine/valine metabolism

Methylene-tetrahydrofolate

Folic acid

serine/glycine metabolism

Methyltetrahydrofolate methylcobalamin formation

Tetrahydrofolate thymidine biosynthesis

MITOCHONDRIA

CYTOPLASM

Aminolevulinic acid dehydratasezinc-containing enzymePb-sensitive

4 moleculescombine

Uroporphyrinogen III Coproporphyrinogen III

-Aminolevulinate synthasepyridoxal phosphate

Succinyl CoA + Glycine

-Aminolevulinic acid

Porphobilinogen

Coproporphyrinogen III

Protoporphyrin IXFerrochelatasePb-sensitive

HEME

Fe2+

-Aminolevulinic acid (two molecules)

Figure 4. Pathway for synthesis of heme

REGULATION OF HEME SYNTHESIS:

Heme:

diminishes transport of -ALA synthase from cytoplasm to mitochondria after its synthesis

represses the production of -ALA synthase by regulating gene transcription.

inhibits activity of pre-existing -ALA synthase

TEETH FROM PATIENT WITH PORPHYRIA DISORDER

PATIENT WITH PORPHYRIA DISORDER

BLOOD CELLS

LIVER

Bilirubin diglucuronide(water-soluble)

2 UDP-glucuronic acid

Stercobilin excreted in feces

Urobilinogen formed by bacteria

KIDNEY

Urobilin excreted in urine

reabsorbed into blood

via bile duct to intestines

Bilirubin (water-insoluble)

via blood to the liver

INTESTINE

Figure 5. Catabolism of hemoglobin

Biliverdinreductase

CO

Biliverdin IX

Heme oxygenase

Bilirubin (water-insoluble)

NADP+

NADPH

HemeGlobin

Hemoglobin

O2