§3 Common metabolism of amino acids - DOC - DOC by Levone

VIEWS: 12 PAGES: 24

									Chapter 8 Metabolism of amino acids
The major function of amino acids is as the source for protein biosynthesis. The metabolism of amino acid includes catabolism and anabolism. In this chapter we are going to discuss the catabolism of amino acids mainly. §1 Nutritional functions of protein Dietary proteins are required to provide amino acids and nitrogen for the synthesis of tissue proteins. Although the catabolism of the carbon skeleton of protein can release energy, the caloric contribution is not the primary function of these nutrients. The major function of food proteins is to provide amino acids and nitrogen for the synthesis of tissue proteins. 1. Requirement and nutritional value of proteins 1-1 Nitrogen balance Like other body constituents, tissue proteins are constantly degraded and must be replenished by cellular biosynthesis. A deficiency in dietary protein will affect protein synthesis of these tissues. The turnover of body protein is a normal process. Nitrogen balance is simply a comparison between the intake of nitrogen (chiefly in the form of protein) and the excretion of nitrogen (chiefly in the form of undigested protein in the feces, urea and ammonia in the urine and sweat, sloughed skin, hair, and nails). In other words, nitrogen balance is the equilibrium between nitrogen incorporated into protein and the amount excreted in urine or lost in skin, sweat, feces. Nitrogen balance can be found to have 3 forms:  General nitrogen balance The losses of nitrogen just balanced by intake. The amount of
1

nitrogen intake is similar to the amount of nitrogen excretion.  Negative nitrogen balance Output of nitrogen exceeds its intake. This condition occurs during illness, wasting diseases (trauma, fever, tuberculosis etc), or starvation.  Positive nitrogen balance Intake exceeds output. This condition can be found in growing children, pregnant woman, convalescing adult, after a debilitating disease. 1-2 Protein quality The synthesis of protein can occur only when all 20 amino acids are readily available for polypeptide formation. The source of amino acids for protein synthesis is the body pool, formed from the releasing of normal breakdown of body protein, and from the digestion of dietary protein, and from the synthesis of some new amino acids. 1) Of those at least 8 amino acids must be supplied by the diet. These are lysine (Lys) leucine (Leu) isoleucine (Ile) tryptophan (Trp) threonine (Thr) methionine (Met) phenylalanine (Phe) valine (Val)

Those amino acids are termed essential amino acids. Essential amino acids are those amino acids that can not be synthesized by the body. 2) non-essential amino acids are amino acids except essential amino acids. Those amino acids can be synthesized by the body. Essential and non-essential amino acids all are important for protein synthesis. The only difference is whether they can be synthesized in
2

the body. 3) The nutritional value of dietary protein depends not only on the quantity of protein available, but also on the quality of protein intake. Protein quality refers to the extent of concentrations and the patterns of essential amino acids in diet conform to their concentrations and the patterns in the body protein. The protein quality is how well the dietary protein can be used to synthesize our body protein. Protein with high quality contains high concentration and suitable pattern of essential amino acids. In general, animal protein contains all the essential amino acids in about sufficient quantity and high quality. Vegetable protein, on the other hand, often lacks one or more essential amino acids, and may, in some cases, be more difficult to digest. Vegetarian diets can provide adequate protein by two ways. ① Enough extra protein is consumed to provide sufficient quantities of the essential amino acids; ② Two or more proteins are consumed together which complement one another in amino acid contents. For example, if corn (deficient on lysine) is combined with legumes (deficient in methionine but rich in lysine), the nutritional value can approach that of animal protein. That is protein complement. 1-3 Protein requirement Amino acids are not stored to any significant extent and must be supplied through regular protein intake. Assuming that the ingested proteins contain the necessary amounts of essential amino acids, the minimal protein requirement is 0.3-0.4 gram per kilogram of body weight per day. Because of the protein quality and the variations in individual physical activities, in 1985, the Nutritional Society of
3

China recommended that 1-2 gram of protein per kilogram of body weight per day. During infancy and early development, greater amounts of proteins must be ingested in order to provide for tissue growth. For example, about 2.2 gram of protein per kilogram of body weight should be furnished daily during the first 6 months of infancy. In the period from the age of 6 months to 1 year, approximately 1.8 gram of protein are required per kilogram of body weight per day. §2 Digestion, Absorption and Putrefaction 1. Digestion In order to be absorbed and utilized, dietary proteins must be digested and degraded to amino acids. This function is performed by proteolytic enzymes. 1-1 In stomach Pepsin(ogen) (endopeptidase) for gastric digestion Activator: hydrochloric acid (HCl), pepsin. 1-2 In intestine Pancreatic juice Trypsin(ogen) (endopeptidase) Chymotrypsin(ogen) (endopeptidase) (pro)Carboxypeptidase (exopeptidase) (pro)elastase (endopeptidase) Intestinal mucosa aminopeptidase(exopeptidase) dipeptidase 2. Absorption 1) The major mechanism includes carriers. Carriers are Na+ dependent. Na+ then is pumped out mucosal cell by Na+-K+
4

-ATPase. 2) γ-glutamyl cycle Enzyme: γ-glutamyl transpeptidase Glutamyl donor: glutathione, Acceptor: amino acid Product: γ-glutamyl amino acid
ATP Gly Cys- Gl y Cys ATP

gl ut at hi one am no aci d i

γ - gl ut am - cyst ei n yl

γ - gl ut am yl t r anspept i dase

γ - gl ut am - am no aci d yl i am no aci d i 5' - oxopr ol i ne ( pyr ogl ut am e) at ATP

gl ut am e at

Powerpoint 1γ-glutamyl cycle 3. Putrefaction Most ingested food is absorbed from the small intestine. The residue passes into the large intestine (colon). There considerable absorption of water takes place, and considerable bacterial activity occurs. The decomposition of proteins and unabsorbed amino acids by anaerobic organisms in the colon is termed putrefaction. The major reactions are decarboxylation and deamination. ① Formation of amines

Lysine (6C) decarboxylation cadaverine Ornithine(5C) Tryptophan Histidine
5

putrescine tryptamine histamine

Most of those amines are powerful vasopressor substances, toxic amines.
Tyrosine tyramine

② Formation of phenol
Tyrosine  tyramine  phenol

③ Formation of indole
Tryptophan  indole

④ Formation of hydrogen sulfide Cysteine

N H

H2S, CO2, methane

⑤ Formation of ammonia
amino acid deamination acid + NH 3

urea hydrolysis CO2 + NH 3

Powerpoint 2 putrefaction §3 Common metabolism of amino acids Amino acids metabolism includes several major topics of medical interest: protein synthesis and degradation , conversion of the carbon
income
digestion absorption

outcome
deamination
NH 3

urea amino acids other nitrogen containing compounds
CO2 + H2O +energy

dietary proteins

degradation tissue proteins biosynthesis of non-essential amino acids

AMINO ACID POOL ¦Á -keto acid decarboxylation amines

carbohydrate fat non-essential amino acids

metabolism of individual amino acids tissue proteins

Powerpoint 3 amino acid pool

non-protein derivatives porphyrins purines pyrimidines neurotransmitters hormones others
6

skeletons of amino acids to other compounds, urea synthesis, and formation of a variety of physiologically active compounds. In this chapter, we will first consider the metabolic pathways for degradation and interconversion of amino acids including the remove of amino nitrogen from amino acids and conversion of the nitrogen to urea. Then we will discuss the relationship of the metabolic pathways between carbohydrate, triacylglycerol and amino acids. We will also consider the metabolism of some specific amino acids. 1. Deamination of amino acids The first stage in the catabolism of almost amino acids is the deamination to form α-ketoacids. There are several pathways to do the deamination, combined deamination is the major pathway to do so. The process is that under the catalysis of transaminase, amino acid reacts with -ketoglutarate at first to form corresponding -keto acid and glutamate; then under the catalysis of L-glutamate dehydrogenase glutamate deaminates to form free ammonia and -ketoglutarate again. The latter can continue to do the next turn of combined deamination. 1-1 Transamination Most amino acids metabolism occurs in the liver. The kidney also participate, but to a much less degree. The contribution of skeletal muscle to amino acid catabolism is minimal. Transamination, catalyzed by enzymes termed transaminases or aminotransferases, is the interconversion between a pair of amino acids and a pair of corresponding -ketoacids.
COOH CH2 CH2 CHNH2 COOH R C=O COOH

glutamate
COOH CH2 CH2 C=O COOH

¦Á-keto acid
R C=O COOH

amino acid

¦Á-ketoglutarate

The transamination system containing glutamate is the most
7

important way of deaminating amino acids. This reaction is reversible. There are two specific transaminases use glutamate as one of their substrate: glutamate pyruvate alanine transaminase (GPT, or alanine transaminase, ALT) and glutamate oxaloacetate transaminase (GOT, or aspartate transaminase, AST). Alanine transaminase catalyzes the transamination between glutamate and pyruvate or -ketoglutarate and alanine. Aspartate transaminase catalyzes the transamination between glutamate
¦Á-ketoglutarate
alanine

glutamate

pyruvate

and oxaloacetate or aspartate and -ketoglutarate. This two enzymes are present in heart and liver tissues relatively at high concentration. Damage of these organs can lead the release of these enzymes into blood stream. That is the basis for diagnosing the damage of heart and liver cells.  The mechanism of transamination Nearly all amino acids, except lysine, threonine and proline, can be undergo transamination.
HCO R-CH-COOH NH2 amino acid HO CH2OPO3H2 COOH (CH2)2 CHNH2 COOH glutamate COOH (CH2)2 C=O COOH ¦Á -ketoglutarate

glutamate ¦Á-ketoglutarate

oxaloacetate aspartate

N H3C pyridoxal phosphate H2C-NH2

R-CH-COOH O ¦Á -keto acid

HO H3C N

CH2OPO3H2

pyridoxamine phosphate

Powerpoint 4 effect of pyridoxal phosphate Pyridoxal phosphate and pyridoxamine phosphate are the coenzyme of transaminases, they play an important role in transfering amino group.
8

At first, pyridoxal phosphate receives an amino group from an amino acid to form pyridoxamine phosphate. Then the latter gives amino group to an -keto acid and returns to pyridoxal phosphate again. 1-2 Oxidative deamination of L-glutamate The transamination of amino acids just tranfers the amino group from an amino acid to an -keto acid forming another new amino acid, there is no liberation of ammonia. That is, there is actually no any release of free ammonia from amino acid. So, it is considered that the deamination of amino acids is mainly accomplished by a cooperation of two or more enzymes. These reactions for releasing ammonia from amino acids are termed as the combined deamination. L-glutamate dehydrogenase catalyzes the release of amino nitrogen as ammonia from glutamate. This enzyme has high activity and widely distributes in mammalian tissues. Liver L-glutamate dehydrogenase is an allosteric enzyme, GTP and ATP are its allosteric inhibitors, GDP and ADP are its allosteric activators, this enzyme is NAD+ dependant.
COOH CH2 CH2 CHNH 2 COOH H2O NAD+ NADH+H+ COOH CH2

glutamate dehydrogenase

CH2 C=o COOH

+ NH 3

glutamate

¦Á -ketoglutarate

This reaction is reversible and functions both in amino acid catabolism and biosynthesis. When transaminase and L-glutamate dehydrogenase combine,an amino acid can gives amino group to -ketoglutarate, to form -keto acid and glutamate. Latter then releases ammonia under
9

the catalysis of L-glutamate dehydrogenase.
COOH R CHNH 2 COOH CH2 CH2 C=o COOH
NH 3

¦Á -ketoglutarate transaminase
COOH R C=O COOH CH2 CH2 CHNH 2 COOH

NADH+H+

glutamate dehydrogenase
NAD+

H2O

glutamate

Powerpoint 5 combined deamination

1-3

Purine nucleotide cycle

In muscle tissue, there is no much L-glutamate dehydrogenase activity. The reactions are catalyzed by a cooperation of a synthesis of aspartate and then adenylosuccinate and adenylate deamination. The overall combined reactions are named " purine nucleotide cycle". Purine nucleotide can be regarded as another kind of combined deamination.
R CHNH 2 COOH
transaminase

COOH CH2 CH2 C=o COOH ¦Á-ketoglutarate COOH CH2 CH2 CHNH 2 COOH glutamate

COOH CH2 CHNH 2 COOH aspartate

O HN N N N R-5'- P IMP H2O NH 2

R C=O COOH

HOOC-CH2-CH-COOH NH N CH2COOH N COCOOH N N oxaloacetate
R-5'- P

NH 2 N N N N
R-5'- P

adenylosuccinate

AMP

CH2COOH CHOHCOOH malate

HOOCCH HCCOOH fumarate

Powerpoint 6 purine nucleotide cycle 2. Metabolism ofα-keto acids 2-1 Forming new amino acids Through the combined deamination, α-keto acids can receive amino group to form new amino acids.
10

In human body the corresponding α-keto acid of essential amino acids can not be synthesized. But when we have the corresponding α-keto acid of essential amino acids, we can get essential amino acids through transamination. 2-2 Oxidation completely to form CO2 and H2O. CO2 + H2O
TCA cycle

For example, α -ketoglutarate → → → → → oxaloacetate → phosphoenolpyruvate →pyruvate 2-3 Conversion to carbohydrate and fat pyruvate, oxaloacetate, α-ketoglutarate, succinate and fumarate can be utilized for the synthesis of glucose by the way of gluconeogenesis. Amino acid converted to these intermediates can be the potential sources of glucose. Such amino acids are termed glucogenic amino acids. Others which can form acetoacetate or
carbohydrate triacylglycerol

Ser

triose- P

¦Á -phosphoglycerol

fatty acid

phosphoenolpyruvate Try Ala Thr Cys Gly Ser Hpr

Ile
acetyl CoA

LEU acetoacetate Try Tyr Lys ketone bodies

pyruvate

Asn

Asp

oxaloacetate

Phe
glutamine

TCA CYCLE
Phe Tyr fumarate ¦Á -ketoglutarate glutamate

His Orn Pro succinyl CoA Val Thr Met Ile

Arg

Powerpoint 7 Interconversion of three metabolic pathways
11

acetyl CoA, are called ketogenic amino acids. Some amino acids are both glucogenic and ketogenic.
Glucogenic: Ala, Arg, Asp, Cys, Glu, Gln, Gly, His, Pro, Met, Ser, Thr, Val. Ketogenic: Lys, Leu. Both: Ile, and three aromatic amino acids (Phe, Trp, Tyr.)

§4 Metabolism of Ammonia metabolism About the metabolism of ammonia, we must know how ammonia gets free from amino acid (combined deamination and purine nucleotide cycle), how ammonia forms (deamination, absorption and hydrolysis of glutamine), how ammonia is transported (as the form of glutamine and alanine), and how ammonia is excreted (NH4+ and urea). 1. Source of ammonia 1) Deamination of amino acids is the major source of ammonia as mentioned above. In addition, amines can be oxidized to form ammonia. amine oxidase RCH2NH2 RCHO + NH3 2) Ammonia is produced by intestinal bacteria from dietary protein and urea. 4g of ammonia may be produced per day. Urea also may be secreted from blood to intestine. Under the alkaline condition, ammonium ions can be converted to ammonia. The latter can easily penetrate the membrane into cells to poison the cell. OH NH4  NH3 3) Kidney produces ammonia and adds it to the blood. This
+

ammonia is produced not from urea, but from intracellular
12

CONH 2

COOH CH2

glutamine.

CH2 CH2 CHNH 2 COOH

glutaminase
H 2O

CH2 CHNH 2 COOH

+

NH 3

glutamine

glutamate

2. Transportation of ammonia Since ammonia is toxic to animal in any significant concentration. Ammonia is constantly produced in the tissue, but is present only in traces in peripheral blood (10-20g/dl). There are two forms of ammonia in blood to be transported into liver and kidney, to produce urea and ammonium salt respectively. The two forms are glutamine and alanine. 2-1 Formation of glutamine Glutamine may be regarded as a temporary nontoxic storage and transport form of ammonia and also the detoxified product of ammonia. Under the catalysis of glutamine synthetase glutamate reacts with ammonia to form glutamine. This reaction is ATP consuming reaction and is irreversible.
COOH CH2 CH2 CHNH 2 COOH NH 3 ATP ADP+Pi Mg 2+ CONH2 CH2 CH2 CHNH 2 COOH

urea liver kidney

NH 4

+

glutamate

glutamine

The glutamine thus formed is transported to the liver for converting the amino group to urea and to the kidney for excretion of its amide-N as ammonium salt (NH4+) in the urine. The enzyme glutaminase catalyzes the hydrolysis:
H2O NH 3 + H

NH4

URINE

glutamine

glutamate

Ammonia is toxic to brain, when its concentration rises, glutamate dehydrogenase catalyzed reaction will be forced backward, and -ketoglutarate in brain drops, the catalytic function of TCA cycle is
13

impaired. No enough energy can be provided to brain. This will cause brain damage.
Failure of liver function  Blood ammonia concentration rises NH3

-ketoglutarateglutamateTCA
cycle is impaired  Energy-consumption of brain falls

 Brain damage  hepatic coma
powerpoint 8 toxic effect of ammonia

2-2 Glucose-alanine cycle In muscle, there is no much glutamine synthetase activity (in muscle, glutamine synthetase is present in only trace amounts). NH3 is added to pyruvate to form alanine by the way of transamination. Alanine is transported through blood stream to liver, where alanine releases NH3 by the way of combined deamination. The pyruvate is converted to form glucose through the gluconeogenesis, and comes back to muscle.
glucose pyruvate glutamate

mainly muscle
corresponding ketoacids branched-chain and other amino acids

alanine

¦Á -ketoglutarate blood

liver
glucose alanine ¦Á -ketoglutarate urea NH 3 NADH+H+
NAD+ H2O

oxaloacetate

pyruvate

glutamate

Powerpoint 9 alanine-glucose cycle 3 Synthesis of urea A moderately active man consuming about 300 gram of
14

carbohydrate, 100 gram of fat, and 100 gram of protein daily must excrete about 16.5 gram of nitrogen daily. 95 % of N is eliminated by kidneys and the remaining 5 % is in feces. The major pathway of nitrogen excretion in human is as urea synthesized in liver, released into blood, and cleared by the kidneys. Urea constitutes 80-90 % of nitrogen excreted. That means that the major fate of NH3 is to form urea. The formation of urea includes the synthesis of carbamoyl phosphate and ornithine cycle. This series of reactions occurs exclusively in the liver.
① Mitochondrial formation of carbamoyl phosphate

Carbamoyl phosphate synthetase I (CPS-I) catalyses the formation of carbamoyl phosphate from ammonia and CO2.
Mg2+ ,AGA

NH3 + CO2 + H2O + 2ATP CPS-I (AGA= N-acetyl glutamate)

H2-N-COO~P + 2ADP+Pi

CPS-I is an allosteric enzyme. N-acetyl glutamate is the allosteric activator.
② The synthesis of citrulline

Carbamoyl phosphate further reacts with ornithine to form citrulline under the catalysis of ornithine transcarbamoylase (ornithine carbamoyl transferase, OCT). This reaction occurs in mitochondria.
③ Arginine synthesis

Citrulline penerates mitochondrial membrane into cytosol, under the catalysis of argininosuccinate synthetase (ASS) citrulline reacts with aspartate to form argininosuccinate. ASS is the rate limiting enzyme of the ornithine cycle. This
15

reaction is ATP-consuming reaction.
④ Then argininosuccinate is split into two molecules: arginine

and fumarate. Of cause fumarate can be hydrated to malate and oxaloacetate. Oxaloacetate can be converted to aspartate by transamination.
⑤ Hydrolysis of arginine to urea and ornithine.

Arginase catalyzes the hydrolysis of arginine to urea. Ornithine formed can now pass back into the mitochondria.
NH 3 + CO2 2ATP carbamoyl phosphate synthetase I (CPS-I) H2O 2ADP+Pi

N-acetylglutamic acid (AGA)

H2N-COO¡« P

carbamoyl phosphate Pi
NH 2 CH2 CH2 CH2 CHNH 2 COOH OCT NH 2 C O NH CH2 CH2 CH2 CHNH 2 COOH

mitochondria cytosol

ornithine

citrulline ornithine
NH 2 C O NH 2 NH 2 C NH NH CH2 CH2 CH2 CHNH 2 COOH COOH CH2 CHNH 2 COOH

citrulline
ATP AMP+PPi ASS

¦Á -ketoglutarate

amino acid ¦Á -ketoacid

aspartate
COOH CH CH2 COOH

glutamate
COOH CH2 C=O COOH

urea
H2O

arginine

NH 2 C N NH CH2 CH2 CH2 CHNH 2 COOH

oxaloacetate

argininosuccinate
HOOCCH HCCOOH

COOH CH2 CHOH COOH

fumarate

malate

Powerpoint 10 ornithine cycle The total reaction is
2NH3 + CO2 + 3ATP + 3H2O  H2N-CO-NH2 + 2ADP +AMP + 4PI

16

§4 Metabolism of some specific amino acids 1. Decarboxylation of amino acids A few amino acids undergo decarboxylation in animal tissues to yield corresponding primary amines, which have special biological functions. Several specific decarboxylases are responsible for catalyzing these reactions. These enzymes require pyridoxal phosphate as the coenzyme and catalyze the removal of carboxyl group as CO2.
RCHNH2COOH CO2 RCH2NH2 decarboxylase (pyridoxal phosphate)

1-1

Formation of γ-aminobutyrate

γ-aminobutyric acid (GABA) as an important physiological active substance in brain is the product of decarboxylation of glutamate. GABA inhibits synaptic transmission.
COOH COOH glutamate CH2 decarboxylase CH2 CH2 CH2 CHNH 2 CH2 CO2 COOH NH 2 glutamate GABA COOH CH2 CH2 COOH succinate

1-2 Formation of taurine

Taurine is formed from cysteine via intermediate sulfoalanine.
CH2 SH CHNH 2 COOH CH2 SO3H CHNH 2 COOH CO2 CH2 SO3H CH2 NH 2

Taurine can combine with bile acids to form conjugated bile acids such as taurocholic acid and taurochenodeoxycholic acid. 1-3 Formation of histamine Histidine decarboxylase is present in mast cells, the major site of histamine formation. Histamine is a powerful vasodilator and in excessive concentrations may cause vascular collapse. Histamine
17

stimulates secretion of both pepsin and acid by stomach and is useful in study of gastric activity. 1-4 Formation of 5-hydroxytryptamine (monooxygenase) is then to 5-hydroxytryptophan, decarboxylated to the yield In brain tryptophan can be hydroxylated by tryptophan hydroxylase 5-hydroxytryptophan

5-hydroxy-tryptamine (serotonin). Serotonin is an important neurotransmitter. It also has additional function in many organs, such as mast cells, platelets, and it causes contraction of smooth muscle in arterioles and bronchioles. 1-5 Formation of polyamines Polyamines can be synthesized from the decarboxylated products of some amino acids. For example, spermidine and spermine can be yield from putrescine produced by a decarboxylation of ornithine.
H2O

urea ornithine

CO2

arginine

putrescine

S-adenosyl methionine 5'-methioadenosine spermine 5'-methio- CO2 adenosine
CO2

spermidine S-adenosyl methionine

Powerpoint 11 formation of polyamines Ornithine can be produced via a hydrolysis of arginine, as described above. Spermidine and spermine are the very important substances for modulating the growth of cells. In regenerating liver, carcinoma tissues, spermary, and embryo, there are high concentrations of spermidine and spermine and increased activity of ornithine decarboxylase. It is assumed that these polyamines promote biosynthesis of nucleic acids and proteins.
18

2. Metabolism of one carbon units 2-1 One carbon unit and tetrahydrofolic acid One carbon units are organic groups containing one carbon atom produced in the catabolism of some amino acids. One carbon units include methyl (-CH3), methylene (-CH2-), methenyl (-CH=), formyl (O=CH-), and formimino (HN=CH-) group. The coenzyme, tetrahydrofolic acid (FH4, THFA) is the carrier of one carbon units. THFA is derived from vitamin folic acid, that is absorbed from intestine.
H2N
N N 1
2 3
4

N
8 5 7 6

N

H CH2 N 9
10

O H C N

COOH CH CH2 CHNH2 COOH
glutamate

OH
2-amino-4-hydroxy6-methylpteridine

p-aminobenzoic acid

pteroic acid

Powerpoint 12 folic acid

folic acid (pteroyl glumanic acid)

The binding forms of one carbon units one carbon units methyl formyl methylene methenyl -CH3 O=CH-CH2=CHformimino HN=CHthe binding points N5-CH3 N5-CH=NH N5-CH=O N10-CH=O N5-CH2-N10 N5=CH-N10

The N5 and N10 nitrogen atoms in the molecule of FH4 participate in the transfer of one carbon units. The binding forms of them with FH4 are listed in the following table. 2-2 The source of one carbon units and the interconversion of one carbon units
19

One carbon units are formed from the catabolism of serine, glycine, histidine, tryptophan and methionine. The methyl group associated with tetrahydrofolate (N5-methyl FH4) is used only in the resynthesis of methionine from homocysteine. The methyl group of methionine is the source of most other methyl groups in the body through transfer reaction of S-adenosyl methionine, such as creatine, epinephrine, choline, DNA and tRNA.
SOURCE INTERCONVERSION USE purine C2

tryptophan
histidine

N -formyl FH4

10

N -formimino FH4

5

N -,N -methenyl FH4

5

10

purine C8

serine glycine (betaine)

N -,N -methylene FH4

5

10

deoxythymidine monophosphate

N -methyl FH4

5

B12

methionine S-adenosyl methionine(SAM)

homocysteine

Powerpoint 13 interconversion of one carbon units
3. Metabolism of sulfur amino acids

provide methyl group to many compounds

Methionine and cysteine are the amino acids containing sulfur. 3-1 Metabolism of methionine 1) transmethylation It has been established that the methyl group of methionine can be transferred only in an active form of methionine, S-adenosyl methionine. The latter is produced under the catalysis of methionine adenosyl transferase. This reaction is energy-consuming reaction.
20

NH 2 N H3C S CH2 CH2 CH NH 2 COOH ATP PPi +Pi N N

methionine adenosyl transferase

H3C

+ S CH2 CH2

N CH2 O H H H H OH OH

CH NH 2 COOH

methionine (Met)

S-adenosyl methionine (SAM)

FH4

methionine

ATP

vit.B12
N5 -CH 3FH4

N5-methyl-FH4 transmethylase

Pi + PPi

homocysteine adenosine

S-adenosyl methionine
RH

H2O

S-adenosyl homocysteine

RCH3

Powerpoint 14 SAM

methionine cycle

SAM has an active methyl group, and SAM is called active methionine. Many compounds can receive the methyl group from SAM, such as choline, creatine, epinephrine. 2) Methionine cycle After SAM gives its active methyl group to an methyl acceptor, it becomes S-adenosyl homocysteine. The latter can be hydrolyzed to yield homocysteine and adenosine. Methionine can be formed from homo-cysteine, the methyl group is from N5-methyl FH4. Vitamin B12 (cobalamin) is the coenzyme of homo-cysteine methyltransferase. When B12 is deficient, not only affect the synthesis of methionine but also affect the utilization of N 5-CH3-FH4. FH4 concentration decreases. 3) Synthesis of creatine Creatine is a very important compound in striated muscle. It is
21

found in a concentration of about 1 gram/ 100 gram tissue, and half of this creatine is combined with phosphate as creatine phosphate. This compound is the storage of phosphate energy to meet the use of contraction. Creatine is synthesized from 3 amino acids, glycine, arginine, and methionine. The transfer of the amidine group from arginine to glycine produces quanidinoacetate and ornithine. Creatine is formed by addition of a methyl group from S-adenosyl methionine. Phosphocreatine is derived from ATP and creatine. As phosphocreatine is used, in muscle, the creatine moiety of the molecule is converted to its anhydride, creatinine, spontaneously and irreversibly. Cratinine has no known function in the body, diffuses from the muscle, and is excreted in the urine as the waste product. In the case of renal failure, the concentration of creatinine will rise.
NH 2 HN C NH + (CH2)3 CHNH 2 COOH arginine CH2NH 2 COOH glycine in kidney NH 2 (CH2)3 CHNH 2 COOH ornithine NH 2 HN C NH + CH2 COOH quanidino-acetate

ADP ATP NH¡« P HN C N CH3 creatine kinase CH2 in muscle COOH creatine phosphate HN=C Pi H3C N NH

NH 2 HN C N CH3 CH2 COOH creatine

liver

S-adenosyl methionine

S-adenosyl homocysteine

C=O C H2 creatinine

H2O

Powerpoint 15 creatine metabolism

3-2 Metabolism of cysteine 1) Conversion of cysteine
NAD + NADH+H +

2 cyst eine

cyst ine

2) Formation of taurine
22

3) Formation of "active sulfate" Sulfate is activated by reacting with ATP to
SO42
a-KETO ACID AMINO ACID

form

3'-phosphoadenosine 5'-phosphosulfate (PAPS).
2H COOH [O] SH2 CH3 O C COOH

NH 2 HS CH2

O C

CH COOH

HS

CH2

cysteine

mercaptopyruvate

pyruvate

ATP + SO4

2

ATP AMP SO3 PPi

ADP 3'- P AMP SO3 PAPS
NH2 N O -O3S O P OH O O H O P OOO H H OH N N N

Powerpoint 16 PAPS sulfate conjugation reactions. ① Formation of glutathione

The active sulfate moiety is also required as the substrate for

Glutathione is a special tripeptide. The N-terminal glutamate is linked to cysteine via a γ-peptidyl bond. Glutathione presents in all forms of life. In human glutathione is required for the activity of several enzymes and of insulin. Glutathione is important in maintaining the sulfhydryl groups of certain proteins in their reduced state by reducing disulfide bonds.
SH CH2 NH 2 -CH-CH2 -CH2 -CO-NH-CH-CO-NH-CH2 -COOH COOH ¦Ã-glut am yl cyst einyl glycine

4. Metabolism of aromatic amino acid The aromatic amino acids include phenylalanine, tyrosine and tryptophan. Tyrosine is a non-essential amino acid, which can be produced from phenylalanine. 1) The metabolism of phenylalanine and tyrosine
23

CH2CHNH 2COOH phenylalanine hydroxylase

CH2CHNH 2COOH

Phe transamination thyroid hormones

OH

tyrosinase

melanin

Tyr dopa

homogentisate phenylpyruvate dopamine

acetoacetate

fumarate

nor-epinephrine

epinephrine catecholamine

Powerpoint 17 phenylalanine and tyrosine Tyrosinase catalyzes the oxidation of tyrosine to form dihydroxyphenylalanine (Dopa). That is the way to melanin. This enzyme is copper-containing enzyme. 2) Metabolism of tryptophan
CH2 CH N NH 2 CH3 COCH2CHCOOH NH 2 OH

tryptophan

kynurenine
OH COOH

NH 2

kynurenate

N

COOH

Ala +
NH 2

N

COOH

anthranilate acetoacetyl C0A
N

OH COOH

xanthurenate

nicotinate

Powerpoint 18 tryptophan 5. Metabolism of branched-chain amino acids Three branched-chain amino acids, valine, leucine, and isoleucine, are essential amino acids. They undergo transamination with α -ketoglutarate to yield corresponding branched chainα-ketoacids.
Valine Leucine Isoleucine α-ketoacid α-ketoacid α-ketoacid succinyl CoA acetoacetate + acetyl CoA acetyl CoA + succinyl CoA April 9, 2002
24


								
To top