3Glucose-6-P

3Ru5P

F6P + E4P + R5P

2 PEP + E4P + R5P

3PG

Serine

Tryptophan + pyruvate + GAP + CO2

Gln

NH3 +

+

+

Aldolase

H

OH

O COO-

H

O

OH

OH

CH2OPO32-

CH2

HO

OH

OH

CH2OPO32-

H

O COO-

P

O

-O

-O

B

2-keto-3-deoxy-arabinoheptulosonate-7-phosphate synthase

CH2

HO

OH

OH

CH2OPO32-

H

O COO-

O

O

COO-

OH

OH

2-O3PO

HB

HNAD+

O COO-

OH

OH

2-O3PO

O

B

H

O COO-

OH

OHO

H-

H+O COO-

OH

OHHO

O COO-

O

OHHO

H

B

O COO-

O

OH

CH2-

HO

H+

COO-

OH

OH

O

HO

chorismatesynthase

COO-

2-O3PO

OH

O R

N

N

NH

N O

O

H

H

R B

COO-

OH

O R

N

N

NH

N O

OH

R

COO-

OH

O R

N

N

NH

N O

OH

R

H

H

COO-

OH

O R

NH

N

NH

N O

O

R H+

H

B

COO-

OH

O COO-

Chorismate

-OOC

O

COO-

OH

Prephenate

PhenylalanineTyrosine

COO-

OH

p-hydroxybenzoate

Coenzyme Q

MeO

MeO

O

O

Me

R

COO-

NH2

p-aminobenzoate

Tetrahydrofolate

COO-

NH2

Anthranilate

Tryptophan

Nictotinamide

COO-

OH

O COO-

NH2

O

RE

S

H

B H+

S

O

E

R

OH-

H+NH3

-O

O

R

H

NH2

B

H+

COO-

O COO-

NH2

H

B

H+

COO-

NH2

Pyruvate

+

Ribose-5-phosphate

Cost = 2 ATP

N

OH OH

O

COO-

2-O3PO H

B

H+

N

OH OH

OH

COO-

2-O3PO

H

HN

OH OH

OH

COO-

2-O3PO

NH

OO-

HO

OH

H

OH

H

CH2OPO32-

H

H+

NH+

O O-OH

CH2OPO32-

OH

H

OH

H

NH

HO CH2OPO32-

OH

H

OH

H

H

B

H+

NH

CH2OPO32-

OH

H

OH

H

N

CH2OPO32-

OH

H

OH

H

H

B

H+

N

CH2OPO32-

OH

H

O

H

H

B

H+

NH

O H

OH

CH2OPO32-

3 glucose + 5NADP+ + 2NAD+ + 2ATP serine + glutamine --->Tryptophan + 5NADPH + 2NADH + 2ADP + 2Pi + GAP + pyruvate + 4CO2 +

glutamate

GAP + glutamate + ATP + 2NADH = serine

glutamine costs NADPH + 2NH4+ + 2ATP

3 glucose + 4NADP+ + 2NH4+ + 4NAD+ + ADP + Pi --->

Tryptophan + 4NADPH + 4NADH + ATP + pyruvate + 4CO2

COO-

OH

O C

CH2

COO-

OH

-OOC H2C C

O

COO-

Chorismate mutase

C

O

COO-

OH

C

O

COO-

O

O

-O-OOC

O

COO-

OHO

-O

H+

O

COO-

OH

H+

O

COO-

prephenate

3 glucose + 2NAD+ + 4NADP+ + NH4+ + ATP --->

phenylalanine + R5P + 4NADPH + 2NADH + 4CO2 + ADP + Pi

3 glucose + 3NAD+ + 4NADP+ + NH4+ + ATP --->

tyrosine + R5P + 4NADPH + 3NADH + 4CO2 + ADP + Pi

In animals tyrosine is made from phenylalanine by phenylalanine hydroxylase

Tyrosine production from phenylalanine

N

N

NH

HN

O

H2N

R

Fe2+

OO

HB

N

N

NH

HN

O

H2N

R

Fe2+

-OO H

A

N

N

NH

HN

O

H2N

R

Fe4+

O2-

OH

N

N

N

HN

O

H2N

R

OH

H

A H

BH

A

HN

N

N

HN

O

HN

R

N

C

O

NH2

R

H H

AH

HN

N

NH

HN

O

H2N

R

N+

C

O

NH2

R

H C

COO-

NH3+

CH2

Fe4+

O2-

H C

COO-

NH3+

CH2 Fe2+

O

H A

H C

COO-

NH3+

CH2

C+ H

OH

H C

COO-

NH3+

CH2 C+

OH

H C

COO-

NH3+

CH2 C

OH+

H

HB

H C

COO-

NH3+

CH2 OH

Tryptophan: indolamine-2,3-dioxygenase

H C

COO-

NH3+

CH2

NH

N

Fe2+

N

N N

O2

H C

COO-

NH3+

CH2

N

N

Fe2+

N

N N

O

O

H C

COO-

NH3+

CH2

N

H C

COO-

NH3+

CH2

N

N

Fe2+

N

N N

H

H

N

Fe2+

N

N N

O

O H

O

OH C

COO-

NH3+

CH2

N

HO

O

N-formylkynurenine

N

Fe3+

N

N N

O

O-

H C

COO-

NH3+

CH2

N

H

H C

COO-

NH3+

CH2

N

HO

O

N-formylkynurenine

AmideHydrolysis

H C

COO-

NH3+

CH2

H2NO

C

O

H O-

Formate

N-formylkynurenine formamidase

Kynurenine

CO

H

O-

Formate

-O P

O

O-

O ADP

C

O

H O P

O

O-

O-

ADP

C

O

H

OP

O

-OO-

NH

HN

N R

B

H

NH

HN

N R

C

O

H

N10-formyl-THF

Loss of ATP!

N10-formyl-THF synthetase

Kynurenine-3-hydroxylase (monooxygenase)

NH

N

NH

N-

R

O

O

NH

N

NH

N-

R

O

O

O

O

NH

N

NH

N-

R

O

O

O

O

H+

NH

N

NH

N

R

O

O

O

OH

NH2

C

O

CH2 C

NH3+

H

COO-

N

N

NH

N

R

O

OHO

O

H

HA

+HCNH2

C

O

CH2 C

NH3+

H

COO-

N

N

NH

N

R

O

OHHO

HO H

B

NH2

C

O

CH2 C

NH3+

H

COO-

OH

C- NH2+

C

O

CH2 C

NH3+

H

COO-

H NH2+

C

O

CH2 C

NH3+

H

COO-

HO H

Kynurenine

3-hydroxykynurenine

N

N

NH

N

R

O

OHHO

B

H

A

N

N

NH

N

R

O

O

FAD

Lose 1 NADPH!

NH2

C

O

CH2 C

COO-

NH3+

H

OH

NH+

CH O

O-

2-O3PO

Schiff BaseFormation

NH2

C

O

CH2 C

COO-

NH+

H

OH

NH+

CH

O-

2-O3PO

B NH2

C

O

CH2 C

COO-

NH+

OH

NH

CH

O-

2-O3PO

Kynureninase

NH2

C

O

CH2 C

COO-

NH+

OH

NH

CH

O-

2-O3PO

NH2

C

O

H2C C

COO-

NH

OH

NH

HC

O-

2-O3PO

O-

3-hydroxy-anthranilate-OH

AH

H3C C

COO-

NH+

NH

HC

O-

2-O3PO

H A H C

COO-

NH+

NH+

HC

O-

2-O3PO

CH3

+

Schiff BaseHydrolysis

H C

COO-

NH3+

CH3

NH+

C

O-

2-O3PO

OH

Alanine

So…Trp = alanine - ATP - NADPH + 3-hydroxyanthranilate

If: Ala = 13 ATP

Then: Trp = 12 ATP - NADPH + 3-hydroxyanthranilate

His

Fe2+

HisO

OH2OH2

O HO

H2N

COO-

O2

O O

His

Fe2+

His

O-O

HO

NH2

COO-

O- O

His

Fe3+

His

O-O

HO

NH2

COO-

O- O

His

Fe2+

His

O-O

HO

NH2

+

COO-

O- O

His

Fe2+

His

O-O

O

NH2

+

COO-

HB

O- O

His

Fe2+

His

O-O

O

NH2

+

COO-

His

Fe2+

His

O-O

OO

-OOC

NH2

O-H

H+H

B

2-amino-3-carboxymuconate-6-semialdehyde

3-hydroxyanthranilate dioxygenase

OO

-OOC

NH

-OH

HA

NH

COO-

COO-

HO

HH

BH

A

N

COO-

COO-

If you need nictotinamide it ends here

OO

-OOC

H2N

-OH

N

COO-

COO-

Non-enzymatic

NH+

C

O

NH2

2-amino-3-carboxymuconatesemialdehyde dehydrogenase

Mechanism and cofactorcompletely unknown

NAD+

-OOCO NH2

-OOCO NH2

COO-

=

Further degradation

Assume loss of NADH

-OOCO NH2 HC

O

C

O

O-

NH2

N+

C

O

H

SH

E

B

HC

O-

C

O

O-

NH2

S

E

C

O

C

O

O-

NH2

S

E

N

C

O

H

R

-O

H

B

C

O

C

O

O-

NH2

-O

H

A

2-aminomuconate

NADH

NAD+

C

O

C

O O-

NH2

-O

2-aminomuconate

OH

BA

H

C

O

C

O O-

NH2

-OO

HH

BAH

-O

OO

O-O

N

CH2N

O

R

H H

HA

-O

OO

O-O

N+

CH2N

O

RNADP+ NADPH

α-ketoadipate

Trp = 12 ATP - 2 NADPH - (NADH?) + NADH + α-ketoadipate + NH3

+ NH3

CH2

CH2

C O

COO-S

C-

N+X

Y

R

S

C

N+X

Y

R

C

CH2

CH2

O-

C

O-OS

C

NX

Y

R

C

CH2

CH2

O-

CO2

SS

H A

S

C

N+X

Y

R

C

CH2

CH2

O-

HSS

S

C-

N+X

Y

R

C

CH2

CH2

O

HSS

HS

CoAB

H2C CH2 C

O

S CoA

HSS-

Glutaryl-CoA

CH2

COO-

CH2

COO-

CH2

COO-

CH2

COO-

CH2

COO-

CH2-OOC

α-ketoadipate dehydrogenase Same mechanism as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.

SS-H

N+

C

O

NH2

SS

N

C

O

NH2

α-ketoadipate = NADH + glutaryl-CoA

CH CH C

O

S CoA

Glutaryl-CoA

CH2-OOC

H

H

B

N

N

NH

N

R

O

O

HA

NH

N

NH

HN

R

O

O

FAD FADH2

C C C

O

S CoACH2-OOC

H

H

Glutaconyl-CoA

α-ketoadipate = NADH + FADH2 + glutaconyl-CoA

C C C

O

S CoACH2C

H

H

Glutaconyl-CoA

O

-O CH CH C

O-

S CoACH2

CO2

AH

C

O

S CoA

H

H

H3C

Crotonyl-CoA

C

O

S CoA

H

H

H3C

Crotonyl-CoA

HO

H

BH

A

C

O

S CoACH2

CH3

H

HO

β-hydroxybutyryl-CoA

α-ketoadipate = 2 NADH + FADH2 + Acetoacetyl-CoA

C

O

S CoACH2

CH3

H

O

β-hydroxybutyryl-CoA

H

B

N+

C

H2N

O

R

C

O

S CoACH2

O

H3C

N

C

H2N

O

R

Acetoacetyl-CoA

C

O

S CoACH2

O

H3C

Acetoacetyl-CoA

H

SCoA

B

C

O

S CoACH2

O-

H3C

SCoA

C

O-

S CoACH2

O

H3C

SCoA

AH

C

O

S CoACH3

2

α-ketoadipate = 2 NADH + FADH2 + 2 Acetyl-CoA

So…Trp = 12 ATP - 2 NADPH + NH3+ α-ketoadipate

If: α-ketoadipate = 2 NADH + FADH2 + 2 Acetyl-CoA

If: Acetyl-CoA = 3 NADH + FADH2 + GTP

Then: α-ketoadipate = 8 NADH + 3 FADH2 + 2 GTP

If GTP = ATP, NADH = 3 ATP FADH2 = 2 ATP and NH3 = -2 ATP

Then: Trp = 12 ATP + 8 NADH + 3 FADH2 + 2 GTP - 2 NADPH + NH3

Remember malate dehydrogenase + malic enzyme converts NADH + NADP+ ---> NAD+ + NADPHSo….-2 NADPH = -2 NADH

Then: Trp = 12 ATP + 6 NADH + 3 FADH2 + 2 GTP + NH3

Then: Trp = 36 ATP + N10-formyl-THF

Tyrosine and phenylalanine degradation

N

N

NH

HN

O

H2N

R

Fe2+

OO

HB

N

N

NH

HN

O

H2N

R

Fe2+

-OO H

A

N

N

NH

HN

O

H2N

R

Fe4+

O2-

OH

N

N

N

HN

O

H2N

R

OH

H

A H

BH

A

HN

N

N

HN

O

HN

R

N

C

O

NH2

R

H H

AH

HN

N

NH

HN

O

H2N

R

N+

C

O

NH2

R

H C

COO-

NH3+

CH2

Fe4+

O2-

H C

COO-

NH3+

CH2 Fe2+

O

H A

H C

COO-

NH3+

CH2

C+ H

OH

H C

COO-

NH3+

CH2 C+

OH

H C

COO-

NH3+

CH2 C

OH+

H

HB

H C

COO-

NH3+

CH2 OH

H C

COO-

NH3+

CH2 OH -OOC C

O

CH2 OH

C CH2 OH

Fe2+

O

CO- O

OO

C CH2 OH

Fe3+

O

CO- O

OO

C CH2 OH

Fe4+

O-

CO- O

O-

O

C CH2 OH

Fe4+

O-O2-

O

+ CO2

C CH2

+HC

OH

Fe2+

O-

O

O-

OH

CH2C

O

-O

O

HB

HA

OH

CH2C

O

-O

HO

OH

CH2C

O

O-

O-

Fe2+

OO

OH

CH2C

O

O-

O

Fe2+

O-O

OH

CH2C

O

O-

O

Fe3+

O2-

OH

CH2C

O

O-

O

Fe3+

O2-

O

O

OH

CH2C

O

O-

O

Fe2+O-

O

-O C

O

CH2 C

O

CH

OH

COO-

H

-O C

O

CH2 C

O

CH

OH

H

COO-

-O H

A H

-O C

O

CH2 C

O

CH2

HO

H

COO-

O

H

B

-O C

O

CH2 C

O-

CH2

HO

H

COO-

O

HA

-O C

O

CH2 C

O

CH3

Makes fumarate + acetoacetate at the expense of NADPH and ascorbate

So…Phe = fumarate + acetoacetate - NADPH - Asc + NH3 andTyr = fumarate + acetoacetate - Asc + NH3

If: fumarate = malate

Then: Phe = malate + acetoacetate - NADPH - Asc + NH3 andTyr = malate + acetoacetate - Asc + NH3

If: malate = pyruvate - NADH + NADPH

Then: Phe = pyruvate + acetoacetate - NADH - Asc + NH3 andTyr = pyruvate + acetoacetate - Asc + NH3 - NADH + NADPH

If: acetoacetate = 2 Acetyl-CoA - ATP

Then: Phe = pyruvate + 2 Acetyl-CoA - NADH - Asc + NH3 -ATP andTyr = pyruvate + 2 Acetyl-CoA - Asc + NH3 - NADH + NADPH - ATP

If: pyruvate = 4 NADH + FADH2 + GTP

If: Acetyl-CoA = 3 NADH + FADH2 + GTP

Then: Phe = 9 NADH + 3 FADH2 + 2 GTP - Asc + NH3 andTyr = NH3 + 2 GTP + 3 FADH2 + 9 NADH + NADPH - Asc

Then: Phe = 9 NADH + 3 FADH2 + 2 GTP - Asc + NH3 andTyr = NH3 + 2 GTP + 3 FADH2 + 9 NADH - NADPH - Asc

If: Asc = - NADPH

Then: Phe = 9 NADH + 3 FADH2 + 2 GTP - NADPH + NH3 andTyr = NH3 + 2 GTP + 3 FADH2 + 9 NADH - 2 NADPH

If: NADPH = NADH

Then: Phe = 8 NADH + 3 FADH2 + 2 GTP + NH3 andTyr = NH3 + 2 GTP + 3 FADH2 + 7 NADH

If GTP = ATP, NADH = 3 ATP FADH2 = 2 ATP and NH3 = -2 ATP

Then: Phe = 30 ATPTyr = 27 ATP

Histidine degradation

C C

COO-

NH3+

H

NH

NH

H

B

C CH

-OOC

H

HN

N

Histidine Urocanate

C CH

-OOC N

N

N+

C

O

NH2

R

N

C

O

NH2

R

H

B

H

AH

H2C CH

-OOC N

N

N

C

O

NH2

R

H

O

H

B

HA

H2CH2C

-OOC N

N

N

C

O

NH2

R

HO

H A

N+

C

O

NH2

R

H2CH2C

-OOC HN

N

OH

B

HA

H2C

CH2

COO-

NH

N

O

4-imidazole-5-propionate

HistidineAmmonia

lyase

Urocanase

Urocanase

UrocanaseUrocanase

Urocanase

Imidazolonepropionase

Glutamateformiminotransferase

H2C

CH2

COO-

NH

N

O

4-imidazole-5-propionate

O-

HB

H A

H2C

CH2

COO-

NH

HN

-OOC

N-formiminoglutamate

N

N

H NH

H A

H C

COO-

NH3+

CH2 CH2 COO-

N

N

CH NHHN

N5-formimino-THF

Glutamate

So….Histidine = glutamate + N5-formimino-THF

If: Glu = α-ketoglutarate + NADPH + NH3

Then: His = α-ketoglutarate + NADPH + NH3

If: α-ketoglutarate = 4 NADH + 2 GTP + 2 FADH2 + NADPH

Then: His = 4 NADH +2 GTP + 2 FADH2 + NADPH + NH3

If: NADH = 3 ATPGTP = ATP

FADH2 = 2 ATPNH3 = -2 ATP

Then: His = 16 ATP + NADPH + N5-formimino-THF

Amino acids as precursors for biological molecules

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