DB code: S00316

RLCP classification	3.133.90030.381 : Transfer
CATH domain	3.40.50.620 : Rossmann fold	Catalytic domain
E.C.	2.7.7.1
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
3.40.50.620 : Rossmann fold	S00314 S00549 S00317 S00318 S00315 T00085 T00249 D00300 M00177 M00178 T00106 T00114

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
Q9HAN9	Nicotinamide mononucleotide adenylyltransferase 1	NMN adenylyltransferase 1 EC 2.7.7.1	NP_073624.2 (Protein) NM_022787.3 (DNA/RNA sequence)	PF01467 (CTP_transf_2) [Graphical View]

KEGG enzyme name
nicotinamide-nucleotide adenylyltransferase NAD+ pyrophosphorylase adenosine triphosphate-nicotinamide mononucleotide transadenylase ATP:NMN adenylyltransferase diphosphopyridine nucleotide pyrophosphorylase nicotinamide adenine dinucleotide pyrophosphorylase nicotinamide mononucleotide adenylyltransferase NMN adenylyltransferase

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location	Cofactor
Q9HAN9	NMNA1_HUMAN	ATP + nicotinamide ribonucleotide = diphosphate + NAD(+).	Homohexamer. Interacts with ADPRT/PARP1.	Nucleus.	Divalent metal cations. Magnesium confers the highest activity.

KEGG Pathways
Map code	Pathways	E.C.
MAP00760	Nicotinate and nicotinamide metabolism

Compound table
	Cofactors	Substrates		Products		Intermediates
KEGG-id	C00305	C00002	C00455	C00013	C00003
E.C.
Compound	Magnesium	ATP	Nicotinamide D-ribonucleotide	Pyrophosphate	NAD+
Type	divalent metal (Ca2+, Mg2+)	amine group,nucleotide	amide group,nucleotide	phosphate group/phosphate ion	amide group,amine group,nucleotide
ChEBI	18420 18420	15422 15422	16171 16171	29888 29888	15846 15846
PubChem	888 888	5957 5957	14180 14180	1023 21961011 1023 21961011	5893 5893

1gzuA	Unbound	Unbound	Bound:NMN	Unbound	Unbound
1gzuB	Unbound	Unbound	Bound:NMN	Unbound	Unbound
1gzuC	Unbound	Unbound	Bound:NMN	Unbound	Unbound
1kkuA	Unbound	Unbound	Unbound	Unbound	Unbound
1kqnA	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqnB	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqnC	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqnD	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqnE	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqnF	Unbound	Unbound	Unbound	Unbound	Bound:NAD
1kqoA	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kqoB	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kqoC	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kqoD	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kqoE	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kqoF	Unbound	Unbound	Unbound	Unbound	Analogue:DND
1kr2A	Unbound	Unbound	Unbound	Unbound	Analogue:TAD
1kr2B	Unbound	Unbound	Unbound	Unbound	Analogue:TAD
1kr2C	Unbound	Unbound	Unbound	Unbound	Analogue:TAD
1kr2D	Unbound	Unbound	Unbound	Unbound	Analogue:TAD
1kr2E	Unbound	Unbound	Unbound	Unbound	Analogue:TAD
1kr2F	Unbound	Unbound	Unbound	Unbound	Analogue:TAD

Reference for Active-site residues
resource	references	E.C.
literature [3]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1gzuA	HIS 24;LYS 57;ARG 227			SER 16
1gzuB	HIS 24;LYS 57;ARG 227			SER 16
1gzuC	HIS 24;LYS 57;ARG 227			SER 16
1kkuA	HIS 24;LYS 57;ARG 227			SER 16
1kqnA	HIS 24;LYS 57;ARG 227			SER 16
1kqnB	HIS 24;LYS 57;ARG 227			SER 16
1kqnC	HIS 24;LYS 57;ARG 227			SER 16
1kqnD	HIS 24;LYS 57;ARG 227			SER 16
1kqnE	HIS 24;LYS 57;ARG 227			SER 16
1kqnF	HIS 24;LYS 57;ARG 227			SER 16
1kqoA	HIS 24;LYS 57;ARG 227			SER 16
1kqoB	HIS 24;LYS 57;ARG 227			SER 16
1kqoC	HIS 24;LYS 57;ARG 227			SER 16
1kqoD	HIS 24;LYS 57;ARG 227			SER 16
1kqoE	HIS 24;LYS 57;ARG 227			SER 16
1kqoF	HIS 24;LYS 57;ARG 227			SER 16
1kr2A	HIS 24;LYS 57;ARG 227			SER 16
1kr2B	HIS 24;LYS 57;ARG 227			SER 16
1kr2C	HIS 24;LYS 57;ARG 227			SER 16
1kr2D	HIS 24;LYS 57;ARG 227			SER 16
1kr2E	HIS 24;LYS 57;ARG 227			SER 16
1kr2F	HIS 24;LYS 57;ARG 227			SER 16

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[1]	p.8527-8529
[5]	p.13508-13509

References
[1]
Resource
Comments
Medline ID
PubMed ID	11751893
Journal	J Biol Chem
Year	2002
Volume	277
Pages	8524-30
Authors	Garavaglia S, D'Angelo I, Emanuelli M, Carnevali F, Pierella F, Magni G, Rizzi M
Title	Structure of human NMN adenylyltransferase. A key nuclear enzyme for NAD homeostasis.
Related PDB	1kku
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID	11788603
Journal	J Biol Chem
Year	2002
Volume	277
Pages	13148-54
Authors	Zhou T, Kurnasov O, Tomchick DR, Binns DD, Grishin NV, Marquez VE, Osterman AL, Zhang H
Title	Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.
Related PDB	1kqn 1kqo 1kr2
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID	11959140
Journal	FEBS Lett
Year	2002
Volume	516
Pages	239-44
Authors	Werner E, Ziegler M, Lerner F, Schweiger M, Heinemann U
Title	Crystal structure of human nicotinamide mononucleotide adenylyltransferase in complex with NMN.
Related PDB	1gzu
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID	12068016
Journal	J Biol Chem
Year	2002
Volume	277
Pages	33291-9
Authors	Singh SK, Kurnasov OV, Chen B, Robinson H, Grishin NV, Osterman AL, Zhang H
Title	Crystal structure of Haemophilus influenzae NadR protein. A bifunctional enzyme endowed with NMN adenyltransferase and ribosylnicotinimide kinase activities.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID	12574164
Journal	J Biol Chem
Year	2003
Volume	278
Pages	13503-11
Authors	Zhang X, Kurnasov OV, Karthikeyan S, Grishin NV, Osterman AL, Zhang H
Title	Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis.
Related PDB
Related UniProtKB

Comments
This enzyme is homologous to the archaeon enzyme (see S00549 in EzCatDB). However, the catalytic residues, which are involved in transition-state stabilization, seem to be different from those from the counterpart enzymes. According to the literature [1] and [5], the reaction proceeds as follows: (1) The 5'-phosphate group of NMN makes a nucleophilic attack on the alpha-phosphoryl group of ATP, from the opposite side of the pyrophosphate leaving group (beta- and gamma-phosphate groups). (2) The transition state seems to be stabilized by the second conserved histidine residue of (T/H)XXH motif, and positively charged residues, such as His24, Lys57 and mainchain amide of Ser16, which are surrounding the alpha-phosphate group of ATP. (Probably, the leaving group of ATP also seems to be stabilized by the positively charged residues such as His24 and Arg227.) (2') Moreover, magnesium ion, which was observed to be bound to the three phosphate groups (alpha-, beta- & gamma-phosphate) in some crystal structures, also plays a role in catalysis, by stabilizing the transition state, and by weakning the alpha-beta phosphate bond of ATP. Thus, this enzyme active site orients the reacting partners, ATP and NMN, in proper positions for the direct reaction to occur, whilst neither acid/base nor nucleophile from enzyme residues have been implicated in the catalytic reaction (see S00549 in EzCatDB).

Comments

This enzyme is homologous to the archaeon enzyme (see S00549 in EzCatDB). However, the catalytic residues, which are involved in transition-state stabilization, seem to be different from those from the counterpart enzymes.
According to the literature [1] and [5], the reaction proceeds as follows:
(1) The 5'-phosphate group of NMN makes a nucleophilic attack on the alpha-phosphoryl group of ATP, from the opposite side of the pyrophosphate leaving group (beta- and gamma-phosphate groups).
(2) The transition state seems to be stabilized by the second conserved histidine residue of (T/H)XXH motif, and positively charged residues, such as His24, Lys57 and mainchain amide of Ser16, which are surrounding the alpha-phosphate group of ATP. (Probably, the leaving group of ATP also seems to be stabilized by the positively charged residues such as His24 and Arg227.)
(2') Moreover, magnesium ion, which was observed to be bound to the three phosphate groups (alpha-, beta- & gamma-phosphate) in some crystal structures, also plays a role in catalysis, by stabilizing the transition state, and by weakning the alpha-beta phosphate bond of ATP.
Thus, this enzyme active site orients the reacting partners, ATP and NMN, in proper positions for the direct reaction to occur, whilst neither acid/base nor nucleophile from enzyme residues have been implicated in the catalytic reaction (see S00549 in EzCatDB).

Created	Updated
2002-05-02	2010-05-21