G +ATP
CH 3 Palmitoyl-CoA
C
CoA (CH2)14
Nutrients
NAD+
NADH, H+
NADP+
NADPH, H+ ADP, Pi
ATP H2O
O2
CO2
Respiratory chain
Catabolic pathways
Biosynthetic products
Metabolic intermediates Biosynthetic pathways
Fig. 5.5 Metabolic functions of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).
O
N
R NH2
N
N
N
N N+
N+
NH2
C O
NH2
C
O NH2
C P
O O
P O O– O–
2 [H]
2 [H]
NAD(P)+ NAD(P)H
Nicotinamide
OH O OH
Ribose
A
B
OH
O
R
Adenine
Ribose
+ H+ O
R
CH2
H2C O O
G
Fig. 5.4 Structures of nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+).
A, Structures of the coenzymes. For NAD+, R = —H; for NADP+, R = —PO32-. B, The reversible hydrogenation of the nicotinamide portion in NAD and NADP.
61 Coenzymes
N N
NH
N O
N N
NH
N O
O O
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3C N
N
NH
N O
O
N N
NH
N O
O
N NH2
N
N
N
P P
2 [H]
2 [H]
HC OH
O HC OH HC H2C
CH2
OH
A
B
Ribitol
OH OH
O
Adenine
Ribose Dimethyl isoalloxazine
Flavin mononucleotide (FMN)
Oxidized flavin Reduced flavin
Flavin adenine dinucleotide (FAD)
HC OH
O HC OH HC H2C
CH2
OH Ribitol
R R
P O CH2
H H
Fig. 5.6 Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) as hydrogen carriers. A, Structures of the coenzymes. The structure formed from the dimethyl isoalloxazine ring and ribitol is called riboflavin (vitamin B2). B, Hydrogen transfer by the dimethyl isoalloxazine ring of FMN and FAD.
CH2
CH2
HS N
H O
CH2
C
O CH OH
C CH3
CH3
CH2 N CH2
H C
N
OH OH NH2
N
N
N
P O
O O
O
CH2
O– P O
O O–
ADP Pantothenic acid
Cysteamine
Fig. 5.7 Structure of coenzyme A. Pantothenic acid is a vitamin, and cysteamine is derived from the amino acid cysteine.
The thioester bonds have free energy contents similar to the phosphoanhydride bonds in ATP. In biosynthetic reactions, the acid is transferred from CoA to an acceptor molecule. For example, this occurs during acetylation re- actions (the “A” in “coenzyme A” stands for “acetylation”) and in the synthesis of triglycerides (see Chapter 25).
S-ADENOSYL METHIONINE DONATES METHYL GROUPS
Methylation reactions transfer a methyl group (—CH3) to an acceptor molecule. The donor of the methyl group is in most cases S-adenosyl methionine (SAM) (Fig. 5.8), which is synthesized in the body from ATP and the amino acid methionine. The methylation reaction con- verts SAM to S-adenosyl homocysteine (SAH), which can be converted back to SAM in a sequence of reac- tions (see Chapter 28). Like CoA, SAM is a cosubstrate rather than a prosthetic group.
Several other coenzymes participate in enzymatic re- actions. These coenzymes, summarized in Table 5.2, will
be discussed in the context of the metabolic reactions in which they participate.
MANY ENZYMES REQUIRE A METAL ION
Some enzymes contain a transition metal such as iron, zinc, copper, or manganese in their active site.
Most of these metals can participate in electron trans- fer reactions by switching between different oxidation states, for example:
Fe3+
e–
Fe2+
Cu2+ Cu+
G
e–
G
(CH2)2
CH S+ H3C
H3+N COO–
(CH2)2 (CH2)2
H3C S+
S
CH
H3+N COO– H3+N CH COO–
CH3
A
CH2
N
OH OH S-Adenosyl methionine
NH2
N
N
N
O
B
S-Adenosyl methionine (SAM)
S-Adenosyl homocysteine (SAH)
OH + R
Methylation reaction
+ H+ O
+ R
Adenosine Adenosine
Fig. 5.8 S-Adenosyl methionine (SAM) as a methyl group donor. A, Structure of the coenzyme. B, Formation of a methoxyl group in a SAM-dependent methylation.
Table 5.2 Summary of the Most Important Coenzymes
Coenzyme Present as Functions in Vitamin*
Adenosine triphosphate (ATP) Cosubstrate Energy-dependent reactions —
Guanosine triphosphate (GTP) Cosubstrate Energy-dependent reactions —
Uridine triphosphate (UTP) Cosubstrate Activation of monosaccharides —
Cytidine triphosphate (CTP) Cosubstrate Phospholipid synthesis —
Nicotinamide adenine dinucleotide (NAD) and
nicotinamide adenine dinucleotide phosphate (NADP)
Cosubstrate Hydrogen transfers Niacin
Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)
Prosthetic group Hydrogen transfers Riboflavin
Coenzyme A Cosubstrate Acylation reactions Pantothenic acid
S-Adenosyl methionine (SAM) Cosubstrate Methylation reactions —
Heme Prosthetic group Electron transfers —
Biotin Prosthetic group Carboxylation reactions Biotin
Tetrahydrofolate (THF) Cosubstrate One-carbon transfers Folic acid
Pyridoxal phosphate (PLP) Prosthetic group Amino acid metabolism B6
Thiamin pyrophosphate (TPP) Prosthetic group Carbonyl transfers Thiamin (B1)
Lipoic acid Prosthetic group Oxidative decarboxylations —
* The vitamins are discussed in Chapter 29.
63 Coenzymes
In other cases the metal acts as a Lewis acid, or electron-pair acceptor. This occurs in many oxygenase reactions, when ferrous iron (Fe2+) or monovalent cop- per (Cu+) binds molecular oxygen in the active site of the enzyme. Another example is the carbonic anhydrase reaction shown in Fig. 5.9. In this case the electron den- sity on the oxygen of a water molecule is increased by
binding to a zinc ion. This makes the water more reac- tive for a nucleophilic attack on the carbon of CO2.
SUMMARY
Some coenzymes are tightly bound to the enzyme as prosthetic groups, whereas others are soluble cosub- strates. They are required because they offer structural features and chemical reactivities that are not present in simple polypeptides. The more important coenzymes include ATP for energy-dependent reactions; NAD, NADP, FAD, and FMN for hydrogen transfers; coen- zyme A for activation of organic acids; and SAM for methylation reactions. Some enzymes catalyze their reaction with the help of a metal ion in their active site. Some coenzymes contain a vitamin as part of their structure. Therefore nutritional deficiencies of vitamins and metals can impair specific enzymatic reactions.
QUESTIONS
1. Protein kinases are enzymes that phosphorylate amino acid side chains of
proteins in ATP-dependent reactions. A protein kinase can be classified as
A. Oxidoreductase B. Hydrolase C. Isomerase D. Lyase E. Transferase
2. Cyanide is a potent inhibitor of cell respiration that prevents the oxidation of all nutrients.
Therefore cyanide will definitely reduce the cellular concentration of
A. Heme groups B. FADH2 C. CoA D. ATP E. SAM
3. The reaction
Succinyl CoA GDP P
Succinate CoA SH GTP -- ++ ++
®
® ++ ++
i
has a standard free energy change ΔG0′ of
−0.8 kcal/mol. If the free energy content of a phosphoanhydride bond in GTP is 7.3 kcal/
mol, what would be the standard free energy change of following reaction?
Succinyl CoA H O-- ++ 2 ®®Succinate CoA SH++
A. −8.1 kcal/mol B. + 6.5 kcal/mol C. + 8.1 kcal/mol D. −6.5 kcal/mol E. + 0.8 kcal/mol
Hδ+
Oδ–
Hδ+
H
H O
C O
O C O
O
Enzyme Zn2+ GEnzyme Zn2+
Fig. 5.9 Catalytic mechanism of carbonic anhydrase. This enzyme catalyzes the reversible reaction CO2+ H2O ⇌ H2CO3.
65