Adenylyl Cyclase

Adenosine 3':5'-monophosphate (cAMP) modifies cell function in all eukaryotic cells, principally through the activation of cAMP-dependent protein kinase (PKA), but also through cAMP-gated ion channels and guanine nucleotide exchange factors directly activated by cAMP. Cellular levels of cAMP reflect the balance between the activities of adenylyl cyclase (ATP: pyrophosphate lyase, cyclizing; EC 4.6.1.1), that catalyzes formation of cAMP from 5'-ATP, and cAMP phosphodiesterases, that catalyze conversion of cAMP to 5'-AMP.

Adenylyl cyclases occur throughout the animal kingdom and play diverse roles in cell regulation. In bacteria, the enzyme may be regulated in response to nutrients or it may constitute a toxic factor in mammals, as with adenylyl cyclases of B. pertussis, B. anthracis, P. aeruginosa, or Y. pestis.

In mammals, the family of adenylyl cyclases is central to one of the most important signal transduction pathways and includes at least ten isozymes. A soluble form (type X) is regulated by HCO3 , whereas the others are membrane-bound and are regulated physiologically through cell-surface receptors linked via heterotrimeric (αβγ) stimulatory (Gαs) and inhibitory (Gαi) guanine nucleotide-dependent regulatory proteins (G-proteins). Most isozymes are activated by Gαs, but differ in their regulation by Gαi and in the effects of Gβγ. These adenylyl cyclases exhibit a putative topology with two tandem repeats of a 6 membrane spanning region and a ~40 kDa cytosolic region. The two cytosolic domains (C1 and C2) share large conserved regions that interact to form a cleft forming the catalytic active site. N-terminal domains are variable and serve regulatory roles. Gαs activates through interaction with the C2 domain yielding the active enzyme: GTP•αs •C. Inhibition by G-proteins occur by a direct effect of Gαi with the C1 domain or by the recombination of βγ with Gαs.

Adenylyl cyclase activity is altered by numerous agents of physiological and biochemical interest. These include agents that act indirectly, by effects on hormone receptors, on Gαs (e.g. cholera toxin) or Gαi (e.g. pertussis toxin), and agents that act directly on the enzyme, in an isozyme-selective manner. All adenylyl cyclases are inhibited by oxidants and are protected by thiols. Most isozymes are stimulated by forskolin. But only select isozymes are activated by Ca2+-calmodulin or regulated by Ca2+ ions. Others are inhibited by nitric oxide (types I and VI) or proteins associated with myc, and several are regulated by protein kinases A and C.

The cleft formed by adenylyl cyclase C1•C2 domains binds both substrate and forskolin. The active site shares topology and reaction mechanism with guanylyl cyclases, with which there is considerable homology, and with oligonucleotide polymerases. Each catalyzes a cation-dependent attack of the 3'-OH on the α-phosphate of an NTP, with PPi as leaving group. Adenylyl cyclases exhibit a reversible bireactant sequential mechanism in which free divalent cation and cation-5'-ATP serve as substrates and cAMP, metal-PPi, and free divalent cation are products.

Although agents that indirectly activate or inhibit adenylyl cyclases are commonly used in the treatment of disease, e.g. β-adrenoceptor blockers, drugs acting directly on the enzyme have only recently been explored. The main classes of which are derivatives of either forskolin or adenine nucleosides. Adenylyl cyclases are inhibited competitively by substrate analogs, the best of which are β-L-2',3'-dd-5’-ATP (IC50 ~24 nM) and, unexpectedly, MANT-5’-GTPgS. Most are also inhibited by adenine nucleoside 3'-polyphosphates, the most potent of which are 2',5'-dd-3’-ATP (IC50~40 nM) and 2’,5’-dd-3’-A4P (IC50 ~7 nM). These latter compounds belong to a class of inhibitors historically called P(purine)-site ligands, which inhibit via a non-competitive, dead-end, post-transition state mechanism. Inhibition by these ligands occurs with varying sensitivity in all isozymes, save those of bacteria and sperm, and they provide an exquisite means for inhibition of this signal transduction pathway.

Cell permeable inhibitors of adenylyl cyclases comprise nucleosides, their derivatives, and recently described pro-nucleotides. The former are effective in the low micromolar range, whereas pro-nucleotides function as prodrugs, with IC50 values in the nanomolar range. These compounds have been used to lower cellular cAMP levels and to alter function in numerous studies with both isolated cells and intact tissues.

The section and Table below contain accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Activators

Inhibitors

Other Products

  • 1,9-Dideoxyforskolin - biologically inactive forskolin analog, useful as a negative control for forskolin
Isozymea (source) I (bovine) II (rat) III (rat) IV (rat) V (rat)
Structuresb
amino acids:

1134

1090

1144

1064

1262
accession: M25579 M80550 M55075 M80633 M96159
Chromosome 7p12 (human)
11A2 (mouse)
5p15 (human)
13C1 (mouse)  
2p22-24 (human)
12A-B (mouse)
14q11.2 (human)
14D3 (mouse)
3q13.2-q21 (human)
16B5 (mouse)
Tissue Expressionc Brain
Adrenal
Brain
Lungs
Skeletal muscle
Olfactory
Brain
Adrenal
Adipose
Pancreas
Ubiquitous Heart
Brain
Physiological Functiong Neurotransmission
Synaptic plasticity
Memory
Circadian rhythm
Not known Olfactory response to oderants Not Known
Cardiac function
Disease Relevance Adenylyl cyclases mediate signal transduction in all tissues and changes in cellular cAMP levels occur in disease states or may be induced therapeutically in the treatment of disease. Some bacterial toxins raise cAMP levels (cf. Overview). Regulation of type V enzyme may be important in cardiomyopathies or of type VI in mitigating aspects of diabetes. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of some cancers and for treatment of yeast and a broad range of fungal infections and some cancers.
G-αs
G-αi d
G-βh No change
Forskolin Derivatives Rank order of stimulatory potency:
7-deacetyl-forskolin (D3533) ≈ 6-[3-(dimethylamino)propionyl]forskolin i ≈ 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin i ≈ 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin i > 6-acetyl-7-deacetyl-forskolin > 7-deacetyl-7-O-hemisuccinyl-forskolin >> 1,9-dideoxy-forskolin (D3658)i
Ca2+/ Calmodulin No change (↑↓) No change ↓ (no CaM)
PKC/PKA ↑ (PKC) ↑+++ (PKC) ↑ (PKC) ↓ (PKC) ↑ (PKC) ↓ (PKA)
Competitive Inhibitorsj Rank-order of inhibitory potency:
β-L-2',3'-dd-5'-ATP ≈ MANT-5’-GTPγS > MANT-5’-ITPγS > β-D-2',3'-dd-5'-ATP ≈ MANT-5’-ATP >> β-L-5'-ATP > 5'-AP(CH2)PPk
Non-competitive Inhibitors (P-site ligands)k,l Rank-order of inhibitory potency:
2',5'-dd-3'-A4P > 2'-d-3'-A4P > 2',5'-dd-3'-ATP (D0939) > 2',5'-dd-3'-ADP (D0814) ≥ 2'-d-3'-ATP (D6500) > 2',5'-dd-3'-AMP (D0689) ≥ 2'-d-3'-ADP (D6000) ≥ 2’,5’-dd-2F-Ado > 2',5'-dd-Ado (D7408) > 2'-d-2F-Ado ≥ 9-Xyl-Ade > 2'‑d-3'-AMP > 3'-ADP > 3'-AMP > 2'-d-Ado (D7400) = 3'-d-Ado (C3394) > 5'-d-Ado (D1771) > 9-Ara-Ade (A5762) = 9‑THF-Ade (SQ 22,536) (S153) ≥ 9-CP-Ade m (C4479) > Ado (A9251)
Pro-nucleotide Inhibitorsn 2’,5’-dd-3’-AMP-bis(Me-SATE) > 2’,5’-dd-3’-AMP-bis(t-Bu-SATE) > 2’,5’-dd-3’-AMP bis(Ph-SATE)
Other Inhibitors Rank-order of inhibitory potency:
PMEApp = PMEAp(NH)p > polyadenylate > 2',3'-dd-Ado (D1285) = 2-Cl-2',3'-dd-Ado > PMEA > 2‑amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80 (N2165)) > MDL-12,330A (M182)k

 

Isozymea (source) VI (rat) VII (mouse) VIII e (rat) IX (mouse) Xf (human) (soluble)
Structuresb
amino acids:

1180

1099

1248(A), 1218(B),
1182(C)

1353

1610
accession: M96160 U12919 L26986 U30602 AF176813
Chromosome 12q12-13 (human)
15F (mouse)
16q12-13 (human) 8q24 (human) 16p13.3 (human)
16 (mouse)
1q24 (human)
Tissue Expressionc Heart
Kidney
Brain
Liver
Retina
Brain
Platelets
Brain
Lung
Skeletal muscle
Heart
Brain
Testes
Physiological Functiong Hormonal regulation of gluconeogenesis
Cell proliferation
Ethanol dependency Neurotransmission
Synaptic plasticity
Memory
Not known HCO3sensor
Disease Relevance Adenylyl cyclases mediate signal transduction in all tissues and changes in cellular cAMP levels occur in disease states or may be induced therapeutically in the treatment of disease. Some bacterial toxins raise cAMP levels (cf. Overview). Regulation of type V enzyme may be important in cardiomyopathies or of type VI in mitigating aspects of diabetes. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of some cancers and for treatment of yeast and a broad range of fungal infections and some cancers.
G-αs No change
G-αi Not known
↓   No change
G-βh Not known Not known No change
Forskolin Derivatives Rank order of stimulatory potency:
7-deacetyl-forskolin (D3533) ≈ 6-[3-(dimethylamino)propionyl]forskolin i ≈ 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin i ≈ 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin i > 6-acetyl-7-deacetyl-forskolin > 7-deacetyl-7-O-hemisuccinyl-forskolin >> 1,9-dideoxy-forskolin (D3658)i
No change No change
Ca2+/ Calmodulin ↓ (no CaM) No change No change Not known
PKC/PKA ↑(PKC) ↓(PKA) ↑(PKC) Not known Not known Not known
Competitive Inhibitorsj Rank-order of inhibitory potency:
β-L-2',3'-dd-5'-ATP ≈ MANT-5’-GTPγS > MANT-5’-ITPγS > β-D-2',3'-dd-5'-ATP ≈ MANT-5’-ATP >> β-L-5'-ATP > 5'-AP(CH2)PPk
Not known
Non-competitive Inhibitors (P-site ligands)k,l Rank-order of inhibitory potency:
2',5'-dd-3'-A4P > 2'-d-3'-A4P > 2',5'-dd-3'-ATP (D0939) > 2',5'-dd-3'-ADP (D0814) ≥ 2'-d-3'-ATP (D6500) > 2',5'-dd-3'-AMP (D0689) ≥ 2'-d-3'-ADP (D6000) ≥ 2’,5’-dd-2F-Ado > 2',5'-dd-Ado (D7408) > 2'-d-2F-Ado ≥ 9-Xyl-Ade > 2'‑d-3'-AMP > 3'-ADP > 3'-AMP > 2'-d-Ado (D7400) = 3'-d-Ado (C3394) > 5'-d-Ado (D1771) > 9-Ara-Ade (A5762) = 9‑THF-Ade (SQ 22,536) (S153) ≥ 9-CP-Ade m (C4479) > Ado (A9251)
Not known
Pro-nucleotide Inhibitorsn 2’,5’-dd-3’-AMP-bis(Me-SATE) > 2’,5’-dd-3’-AMP-bis(t-Bu-SATE) > 2’,5’-dd-3’-AMP bis(Ph-SATE) Not known
Other Inhibitors Rank-order of inhibitory potency:
PMEApp = PMEAp(NH)p > polyadenylate > 2',3'-dd-Ado (D1285) = 2-Cl-2',3'-dd-Ado > PMEA > 2‑amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80 (N2165)) > MDL-12,330A (M182)k
Not known

 

Footnotes

a) Isozyme source is for structure information.

b) Structures available at http://www.ncbi.nlm.nih.gov

c) Tissue expression is for evidence of protein expression; this is not a complete listing.

d) Empty cells implies no information.

e) Type VIII exhibits three splice variants (A,B,C).

f) Type X adenylyl cyclase is stimulated by HCO3.

g) All adenylyl cyclase isozymes save type X mediate transmembrane regulation of cell function by hormones through altered rates of cAMP formation. The functional consequences of this are thus dependent on tissue-specific receptors and on downstream effectors through which cAMP acts.

h) Effects of G-βγ are on Gαs-stimulated enzyme.

i) 6-[3-(dimethylamino)propionyl]-forskolin (NHK477) exhibits enhanced selectivity for type V adenylyl cyclase; 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin exhibits enhanced selectivity for type II adenylyl cyclase; 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin exhibits enhanced selectivity for type III adenylyl cyclase; 1,9-dideoxy-forskolin does not stimulate.

j) Competitive inhibitors interact with the pre-transition configuration of the enzyme. Isozyme selectivity has not been determined; comparisons are from experiments with a detergent-extract from rat brain.

k) Inhibitory P-site ligands are characteristically adenine nucleosides or nucleoside phosphates that inhibit adenylyl cyclases by a noncompetitive or uncompetitive, dead-end- (post-transition-state) mechanism. This comparison is from experiments with a detergent-extract from rat brain. These ligands likely inhibit all isozymes, though potencies may vary; comparisons have been made only with types I, II, VI, VII, and VIII.

l) Of the cell-permeable 9-substituted adenine derivatives, 9-CP-Ade is the most stable chemically and metabolically.

m) Unprotected nucleotides are not cell-permeable, whereas nucleosides, nucleoside analogs, and the protected (pro-)nucleotides are cell permeable. The 3'-bis(acyl-2'-thioethyl)phosphate derivatives of 2',5'-dd-Ado require intact cells for inhibition of cAMP formation and exhibited IC50 values in intact macrophages or adipocytes comparable to the IC50 values seen with the corresponding nucleoside-3'-triphosphate on isolated adenylyl cyclase from these cells. Rank order of inhibitory potency depends on relative rates of uptake, deprotection, and subsequent processing within cells. For this series, deprotection rates are in the order given.

n) Unprotected nucleotides are not cell-permeable, whereas nucleosides, nucleoside analogs, and the protected (pro-)nucleotides are cell permeable. The 3'-bis(acyl-2'-thioethyl)phosphate derivatives of 2',5'-dd-Ado require intact cells for inhibition of cAMP formation and exhibited IC50 values in intact macrophages or adipocytes comparable to the IC50 values seen with the corresponding nucleoside-3'-triphosphate on isolated adenylyl cyclase from these cells. Rank order of inhibitory potency depends on relative rates of uptake, deprotection, and subsequent processing within cells.

For this series, deprotection rates are in the order given.

 

Abbreviations

Ado: adenosine
2'-d-Ado: 2'-deoxyadenosine
3'-d-Ado: 3'-deoxyadenosine (cordycepin)
5'-d-Ado: 5'-deoxyadenosine
2',5'-dd-Ado: 2',5'-dideoxyadenosine
2',3'-dd-Ado: 2',3'-dideoxyadenosine
9-CP-Ade: 9-(cyclopentyl)-adenine
9-THF-Ade: 9-(tetrahydrofuryl)-adenine (SQ22,536)
9-Ara-Ade: 9-(arabinofuranosyl)-adenine
9-Xyl-Ade: 9-(xylofuranosyl)-adenine
2'-d-3'-AMP: 2'-deoxyadenosine 3'-monophosphate
2'-d-3'-ADP: 2'-deoxyadenosine 3'-diphosphate
2'-d-3'-ATP: 2'-deoxyadenosine 3'-triphosphate
2',5'-dd-3'-AMP: 2',5'-dideoxyadenosine 3'-monophosphate
2',5'-dd-3'-ADP: 2',5'-dideoxyadenosine- 3'-diphosphate
2',5'-dd-3'-ATP: 2',5'-dideoxyadenosine 3'-triphosphate
2',5'-dd-3'-A4P: 2',5'-dideoxyadenosine 3'-tetraphosphate; 5'-APP(CH2)P, adenosine 5'-(βγ-methylene)-triphosphate
βL-5'-ATP: β-L-adenosine 5'-triphosphate; β-L-2',3'-dd-5'-ATP, β-L-2',3'-dideoxyadenosine 5'-triphosphate
PMEA: 9-(2-phosphonylmethoxyethyl)-adenine; PMEApp, 9-(2-diphosphorylphosphonylmethoxyethyl)-adenine
MDL-12,330A: (cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine·HCl; NKY80, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone
2',5'-dd-3'-AMP-bis(Me-SATE): 2',5'-dd-Ado-3'-(acetyl-2-thioethyl)-phosphate; 2',5'-dd-3'-AMP-bis(t-Bu-SATE), 2',5'-dd-Ado-3'-(pivaloyl-2-thioethyl)-phosphate
2',5'-dd-3'-AMP-bis(Ph-SATE): 2',5'-dd-Ado-3'-(phenhyl-2-thioethyl)-phosphate; MANT-5'-GTPγS, 3'-(2')-O-N-methylanthraniloyl-guanosine-5'[γ-thio]triphosphate
MANT-5'-ITPγS: 3'-(2')-O-N-methylanthraniloyl-inosine-5'[γ-thio]triphosphate; MANT-5'ATP, 3'-(2')-O-N-methylanthraniloyl-5'-ATP

 

Isozymea

(Source)

I (bovine)

II (rat)

III (rat)

IV (rat)

V (rat)

Structuresb

Amino acids:

Accession:

 

1134

M25579

 

1090

M80550

 

1144

M55075

 

1064

M80633

 

1262

M96159

Chromosome

7p12 (h)

11A2 (m)

5p15 (h)

13C1 (m)

2p22-24 (h)

12A-B (m)

14q11.2 (h)

14D3 (m)

3q13.2-q21 (h)

16B5 (m)

Tissue Expressionc

Brain

Adrenal

Brain

Lungs

Skeletal

Muscle

Olfactory

Brain

Adrenal

Adipose

Pancreas

Ubiquitous

Heart

Brain

Physiological Functiong

Neurotransmission

Synaptic plasticity

Memory

Circadian rhythm

Not known

Olfactory response to oderants

Not known

Cardiac function

Disease Relevance

Adenylyl cyclases mediate signal transduction in all tissues and changes in cellular cAMP levels occur in disease states or may be induced therapeutically in the treatment of disease. Some bacterial toxins raise cAMP levels. Regulation of type V enzyme may be important in cardiomyopatheis or of type VI in mitigating aspects of diabetes. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of some cancers and for treatment of yeast and a broad range of fungal infections.

G-as

 

 

 

 

 

G-ai

 

 

 

 

 

G-bh

 

 

No change

 

 

Forskolin Derivatives

Rank order of stimulatory potency:

7-deacetyl -forskolin ≈ 6-[3-(dimethylamino)propionyl]forskolin ≈ 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin ≈ 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin > 6-acetyl-7-deacetyl-forskolin > 7-deacetyl-7-O-hemisuccinyl-forskolin >> 1,9-dideoxy-forskolin

Ca2+/Calmodulin

 

No change

 

No change

 

PKC/PKA

(PKC)

+++ (PKC)

(PKC)

(PKC)

(PKC) (PKA)

Competitive Inhibitors

Rank order of inhibitory potency:

B-L-2’,3’-dd-5’-ATP >> MANT-5’-GTPgS > MANT-5’-ITPgS > B-D-2’,3’-dd-5’-ATP >> MANT-5’-ATP >> 5’-AP(CH2)PP

Non-competitive Inhibitors

(P-site ligands)k,l

Rank order of inhibitory potency:

2',5'-dd-3'-A4P > 2'-d-3'-A4P > 2',5'-dd-3'-ATP > 2',5'-dd-3'-ADP; 2'-d-3'-ATP > 2',5'-dd-3'-AMP; 2'-d-3'-ADP; β 2’,5’-dd-2F-Ado > 2',5'-dd-Ado > 2'-d-2F-Ado; 9-Xyl-Ade > 2'‑d-3'-AMP > 3'-ADP > 3'-AMP > 2'-d-Ado; 3'-d-Ado; 5'-d-Ado > 9-Ara-Ade; 9‑THF-Ade (SQ 22,536); β 9-CP-Ade > Ado

Pro-nucleotide Inhibitorsn

2’,5’-dd-3’-AMP-bis(Me-SATE) > 2’,5’-dd-3’-AMP-bis(t-Bu-SATE) > 2’,5’-dd-3’-AMP bis(Ph-SATE)

Other Inhibitors

Rank order of stimulatory potency:

PMEApp; PMEAp(NH)p > polyadenylate > 2',3'-dd-Ado; 2-Cl-2',3'-dd-Ado > PMEA > 2‑amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80) > MDL-12,330A

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Data 1
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Data

       
Therearelongwordsheretoo Longwordsthatmaybelongerthancolumn Morelongwordsthatarelongerthancolumn Evenmorewordsandtheyrelong Longlongwords Whattodoaboutlongwords
           
           
           
           
           
           
           
           
           
           
           
           
           
Isozymea
(Source)
I (bovine) II (rat) III (rat) IV (rat) V (rat)

Structuresb
Amino acids:

Accession:

 

1134

M25579

 

1090

M80550

 

1144

M55075

 

1064

M80633

 

1262

M96159

Chromosome

7p12 (h)

11A2 (m)

5p15 (h)

13C1 (m)

2p22-24 (h)

12A-B (m)

14q11.2 (h)

14D3 (m)

3q13.2-q21 (h)

16B5 (m)

Tissue Expressionc Brain
Adrenal
Brain
Lungs
Skeletal
Muscle
Olfactory
Brain
Adrenal
Adipose
Pancreas
Ubiquitous Heart
Brain
Physiological Functiong Neurotransmission
Synaptic plasticity
Memory
Circadian rhythm
Not known Olfactory response to oderants Not known Cardiac function
Disease Relevance Adenylyl cyclases mediate signal transduction in all tissues and changes in cellular cAMP levels occur in disease states or may be induced therapeutically in the treatment of disease. Some bacterial toxins raise cAMP levels. Regulation of type V enzyme may be important in cardiomyopatheis or of type VI in mitigating aspects of diabetes. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of some cancers and for treatment of yeast and a broad range of fungal infections.
G-as          
G-ai          
G-bh     No change    
Forskolin Derivatives

Rank order of stimulatory potency:
7-deacetyl -forskolin ≈ 6-[3-(dimethylamino)propionyl]forskolin ≈ 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin ≈ 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin > 6-acetyl-7-deacetyl-forskolin > 7-deacetyl-7-O-hemisuccinyl-forskolin >> 1,9-dideoxy-forskolin

Ca2+/Calmodulin       No change  
PKC/PKA (PKC) +++ (PKC) (PKC) (PKC) (PKC) (PKA)
Competitive Inhibitors Rank order of inhibitory potency:
B-L-2’,3’-dd-5’-ATP >> MANT-5’-GTPgS > MANT-5’-ITPgS > B-D-2’,3’-dd-5’-ATP >> MANT-5’-ATP >> 5’-AP(CH2)PP
Non-competitive Inhibitors
(P-site ligands)k,l
Rank order of inhibitory potency:
2',5'-dd-3'-A4P > 2'-d-3'-A4P > 2',5'-dd-3'-ATP > 2',5'-dd-3'-ADP; 2'-d-3'-ATP > 2',5'-dd-3'-AMP; 2'-d-3'-ADP; β 2’,5’-dd-2F-Ado > 2',5'-dd-Ado > 2'-d-2F-Ado; 9-Xyl-Ade > 2'‑d-3'-AMP > 3'-ADP > 3'-AMP > 2'-d-Ado; 3'-d-Ado; 5'-d-Ado > 9-Ara-Ade; 9‑THF-Ade (SQ 22,536); β 9-CP-Ade > Ado
Pro-nucleotide Inhibitorsn 2’,5’-dd-3’-AMP-bis(Me-SATE) > 2’,5’-dd-3’-AMP-bis(t-Bu-SATE) > 2’,5’-dd-3’-AMP bis(Ph-SATE)
Other Inhibitors Rank order of stimulatory potency:
PMEApp; PMEAp(NH)p > polyadenylate > 2',3'-dd-Ado; 2-Cl-2',3'-dd-Ado > PMEA > 2‑amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80) > MDL-12,330A
Isozymea (source) I (bovine) II (rat) III (rat) IV (rat) V (rat) VI (rat) VII (mouse) VIII e (rat) IX (mouse) Xf (human) (soluble)
Structuresb
amino acids:

accession:

1134

M25579

1090

M80550

1144

M55075

1064

M80633

1262

M96159

1180

M96160

1099

U12919

1248(A), 1218(B), 1182(C)

L26986

1353

U30602

1610

AF176813
Chromosome 7p12 (human)
11A2 (mouse)
5p15 (human)
13C1 (mouse)  
2p22-24 (human)
12A-B (mouse)
14q11.2 (human)
14D3 (mouse)
3q13.2-q21 (human)
16B5 (mouse)
12q12-13 (human)
15F (mouse)
16q12-13 (human) 8q24 (human) 16p13.3 (human)
16 (mouse)
1q24 (human)
Tissue Expressionc Brain
Adrenal
Brain
Lungs
Skeletal muscle
Olfactory
Brain
Adrenal
Adipose
Pancreas
Ubiquitous Heart
Brain
Heart
Kidney
Brain
Liver
Retina
Brain
Platelets
Brain
Lung
Skeletal muscle
Heart
Brain
Testes
Physiological Functiong Neurotransmission
Synaptic plasticity
Memory
Circadian rhythm
Not Known Olfactory response to oderants Not Known
Cardiac function Hormonal regulation of gluconeogenesis
Cell proliferation
Ethanol dependency Neurotransmission
Synaptic plasticity
Memory
Not Known HCO3sensor
Disease Relevance Adenylyl cyclases mediate signal transduction in all tissues and changes in cellular cAMP levels occur in disease states or may be induced therapeutically in the treatment of disease. Some bacterial toxins raise cAMP levels (cf. Overview). Regulation of type V enzyme may be important in cardiomyopathies or of type VI in mitigating aspects of diabetes. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of some cancers. Inhibition of adenylyl cyclases may be a useful strategy in combination therapy for treatment of yeast and a broad range of fungal infections and some cancers.
G-αs no change
G-αi d Not Known
↓   No change
G-βh No change Not known Not known No change
Forskolin Derivatives Rank order of stimulatory potency: 7-deacetyl-forskolin (D3533) ≈ 6-[3-(dimethylamino)propionyl]forskolin i ≈ 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin i ≈ 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin i > 6-acetyl-7-deacetyl-forskolin > 7-deacetyl-7-O-hemisuccinyl-forskolin >> 1,9-dideoxy-forskolin (D3658)i       no change no change
Ca2+/ Calmodulin no change (↑↓) no change ↓ (no CaM) ↓ (no CaM) no change no change Not Known
PKC/PKA ↑ (PKC) ↑+++ (PKC) ↑ (PKC) ↓ (PKC) ↑ (PKC) ↓ (PKA) ↑(PKC) ↓(PKA) ↑(PKC) Not known Not known Not Known
Competitive Inhibitorsj Rank-order of inhibitory potency: β-L-2',3'-dd-5'-ATP » MANT-5’-GTPgS > MANT-5’-ITPgS > β -D-2',3'-dd-5'-ATP » MANT-5’-ATP > > β -L-5'-ATP > 5'-AP(CH2)PPk
Not Known
Non-competitive Inhibitors (P-site ligands)k,l Rank-order of inhibitory potency: 2',5'-dd-3'-A4P > 2'-d-3'-A4P > 2',5'-dd-3'-ATP (D0939) > 2',5'-dd-3'-ADP (D0814) β 2'-d-3'-ATP (D6500) > 2',5'-dd-3'-AMP (D0689) β 2'-d-3'-ADP (D6000) β 2’,5’-dd-2F-Ado > 2',5'-dd-Ado (D7408) > 2'-d-2F-Ado β 9-Xyl-Ade > 2'‑d-3'-AMP > 3'-ADP > 3'-AMP > 2'-d-Ado (D7400) β 3'-d-Ado (C3394) β 5'-d-Ado (D1771) > 9-Ara-Ade (A5762) β 9‑THF-Ade (SQ 22,536) (S153) β 9-CP-Ade m (C4479) > Ado (A9251) Not Known
Pro-nucleotide Inhibitorsn 2’,5’-dd-3’-AMP-bis(Me-SATE) > 2’,5’-dd-3’-AMP-bis(t-Bu-SATE) > 2’,5’-dd-3’-AMP bis(Ph-SATE)
Not Known
Other Inhibitors Rank-order of inhibitory potency: PMEApp β PMEAp(NH)p > polyadenylate > 2',3'-dd-Ado (D1285) β 2-Cl-2',3'-dd-Ado > PMEA > 2‑amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80 (N2165)) > MDL-12,330A (M182)k
Not Known

 

Footnotes

a) Isozyme source is for structure information.

b) Structures available at http://www.ncbi.nlm.nih.gov

c) Tissue expression is for evidence of protein expression; this is not a complete listing.

d) Empty cells implies no information.

e) Type VIII exhibits three splice variants (A,B,C).

f) Type X adenylyl cyclase is stimulated by HCO3−.

g) All adenylyl cyclase isozymes save type X mediate transmembrane regulation of cell function by hormones through altered rates of cAMP formation. The functional consequences of this are thus dependent on tissue-specific receptors and on downstream effectors through which cAMP acts.

h) Effects of G-βγ are on Gαs-stimulated enzyme.

i) 6-[3-(dimethylamino)propionyl]-forskolin (NHK477) exhibits enhanced selectivity for type V adenylyl cyclase; 6-[N-(2-isothiocyanatoethyl)aminocarbonyl]forskolin exhibits enhanced selectivity for type II adenylyl cyclase; 5,6-dehydroxy-7-deacetyl-7-nicotinoylforskolin exhibits enhanced selectivity for type III adenylyl cyclase; 1,9-dideoxy-forskolin does not stimulate.

j) Competitive inhibitors interact with the pre-transition configuration of the enzyme. Isozyme selectivity has not been determined; comparisons are from experiments with a detergent-extract from rat brain.

k) Inhibitory P-site ligands are characteristically adenine nucleosides or nucleoside phosphates that inhibit adenylyl cyclases by a noncompetitive or uncompetitive, dead-end- (post-transition-state) mechanism. This comparison is from experiments with a detergent-extract from rat brain. These ligands likely inhibit all isozymes, though potencies may vary; comparisons have been made only with types I, II, VI, VII, and VIII.

l) Of the cell-permeable 9-substituted adenine derivatives, 9-CP-Ade is the most stable chemically and metabolically.

m) Unprotected nucleotides are not cell-permeable, whereas nucleosides, nucleoside analogs, and the protected (pro-)nucleotides are cell permeable. The 3'-bis(acyl-2'-thioethyl)phosphate derivatives of 2',5'-dd-Ado require intact cells for inhibition of cAMP formation and exhibited IC50 values in intact macrophages or adipocytes comparable to the IC50 values seen with the corresponding nucleoside-3'-triphosphate on isolated adenylyl cyclase from these cells. Rank order of inhibitory potency depends on relative rates of uptake, deprotection, and subsequent processing within cells. For this series, deprotection rates are in the order given.

n) Unprotected nucleotides are not cell-permeable, whereas nucleosides, nucleoside analogs, and the protected (pro-)nucleotides are cell permeable. The 3'-bis(acyl-2'-thioethyl)phosphate derivatives of 2',5'-dd-Ado require intact cells for inhibition of cAMP formation and exhibited IC50 values in intact macrophages or adipocytes comparable to the IC50 values seen with the corresponding nucleoside-3'-triphosphate on isolated adenylyl cyclase from these cells. Rank order of inhibitory potency depends on relative rates of uptake, deprotection, and subsequent processing within cells.

For this series, deprotection rates are in the order given.

 

Abbreviations

Ado: adenosine
2'-d-Ado: 2'-deoxyadenosine
3'-d-Ado: 3'-deoxyadenosine (cordycepin)
5'-d-Ado: 5'-deoxyadenosine
2',5'-dd-Ado: 2',5'-dideoxyadenosine
2',3'-dd-Ado: 2',3'-dideoxyadenosine
9-CP-Ade: 9-(cyclopentyl)-adenine
9-THF-Ade: 9-(tetrahydrofuryl)-adenine (SQ22,536)
9-Ara-Ade: 9-(arabinofuranosyl)-adenine
9-Xyl-Ade: 9-(xylofuranosyl)-adenine
2'-d-3'-AMP: 2'-deoxyadenosine 3'-monophosphate
2'-d-3'-ADP: 2'-deoxyadenosine 3'-diphosphate
2'-d-3'-ATP: 2'-deoxyadenosine 3'-triphosphate
2',5'-dd-3'-AMP: 2',5'-dideoxyadenosine 3'-monophosphate
2',5'-dd-3'-ADP: 2',5'-dideoxyadenosine- 3'-diphosphate
2',5'-dd-3'-ATP: 2',5'-dideoxyadenosine 3'-triphosphate
2',5'-dd-3'-A4P: 2',5'-dideoxyadenosine 3'-tetraphosphate; 5'-APP(CH2)P, adenosine 5'-(βγ-methylene)-triphosphate
βL-5'-ATP: β-L-adenosine 5'-triphosphate; β-L-2',3'-dd-5'-ATP, β-L-2',3'-dideoxyadenosine 5'-triphosphate
PMEA: 9-(2-phosphonylmethoxyethyl)-adenine; PMEApp, 9-(2-diphosphorylphosphonylmethoxyethyl)-adenine
MDL-12,330A: (cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine•HCl; NKY80, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone
2',5'-dd-3'-AMP-bis(Me-SATE): 2',5'-dd-Ado-3'-(acetyl-2-thioethyl)-phosphate; 2',5'-dd-3'-AMP-bis(t-Bu-SATE), 2',5'-dd-Ado-3'-(pivaloyl-2-thioethyl)-phosphate
2',5'-dd-3'-AMP-bis(Ph-SATE): 2',5'-dd-Ado-3'-(phenhyl-2-thioethyl)-phosphate; MANT-5'-GTPγS, 3'-(2')-O-N-methylanthraniloyl-guanosine-5'[γ-thio]triphosphate
MANT-5'-ITPγS: 3'-(2')-O-N-methylanthraniloyl-inosine-5'[γ-thio]triphosphate; MANT-5'ATP, 3'-(2')-O-N-methylanthraniloyl-5'-ATP.

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