er B i o F h y s i c a A c t a . 1t28 (1992) 117-131 Igq2 Elsevier Science Publishers B.V. All rights reserved (1111)5-27,5(1/92/S(]5.00

117

Biochimica

Review

BBALIP 54021)

Mammalian lipoxygenases: molecular structures and functions Shozo DeFartment

of Biochemistry,

Tokush#na

Yamamoto Unicersi~' School of Medicine,

Tokushima

(JapanJ

(Received 3 July 1992)

Key words: Lipoxygenase; Cycloo~genase; O,'ojgcnase; Arachidonic acid; Hydroperoxide: Prostaglandin; Leukotriene; Enzyme immunoassay: Complementary. DNA

Contents I.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

117

II,

Stereochemistryof lipoxygenase reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Stereospecificity of hydrogen elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Steieospecificity of oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

!18 118 119

III. Lipoxygenases as multi-functional enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119

IV. Substrate specificities of lipo~genases

120

V.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Prosthetic groups and cofactors of lipoxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Peroxi.-le activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. ATP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. 5-Lipoxygenase-activating protein (FLAP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI. Molecular structures of lipoxygenases

. . . . . . . . . . .

............................................

121 t21 121 121 122 IZ3 123

VII. Regulation of arachidonate metabolism by enzyme induction . . . . . . . . . . . . . . . . . . . . . . . . . .

1~

VIII, Distribution of lipoxygenases and cyclooxygenasc in vltriou,, mammalian ti~'~ues .

125

IX. Physiological roles of lipox-ygenases Acknowledgemerits References

.............................................

............................................................

. . . . . . . . . . .

t27 128

..................................................................

128

I. Introduction Correspondence to: S. Yamamoto, Department of Biochemistry, Tokushima University School of Medicine, Kuramoto-cho, Tokushima 770, Japan. Abbreviations: 5-H(P)ETE, 5-hydro(pero)xy-6,8,11,14-eicosatetraenoic acid; 12-H(P)ETE, 12-hydro(pero)x3,-5,8,10,14-eicosatetraenoic acid; 15-H(P)ETE, 15-hydro(pero~y-5,8,11,13-eicosatetraenoic acid; LTAa, leukotriene A+.

L i p o x y g e n a s e s a r e dioxy, g e n a s e s which r e c o g n i z e t h e 1,4-oent~dicftc. ..,,, s t r u c t u r e o f p o l y u n s a t u r a t e d fatty acids a n d i n c o r p o r a t e ~iingle m o l e c u l e s o f o ~ g e n at specific c a r b o n a t o m s o f s u b s t r a t e fatty acids, T h e r e a c t i o n p r o d u c t s a r e h y d r o p e r o x y acids c o n t a i n i n g c o n j u g a t e d d i e n e s (Fig. 1).

118

~

V'~.A.-coo~:

HO0

/,

,

/

~

c

o

o

/'=V=M~c oo.

B(S)*HPETE

t2 (SPHPETE

~

OOH

~i,

15 (S}-HPETE

Cyclootygenas.e Arachtdontc acicl |1$.15.1 I~oxyg,more)]

°'~coo. PGG~

action of lipox~'gcnasc which added oxygen at the C-5 position of arachidonate [8]. More recently, a lipoxygenase which oxygenates C-15 of arachidonic acid has been partially purified from rabbit leukocytes [9] and a lipoxygenase which oxygenates C-8 of arachidonic acid has been chacterized from cytosolic preparations of mouse epidermis treated with phorbol ester [10]. These lipoxygenases are now referred to as arachidonate x-!~poxygenase where x is the carbon position in arachidonate predominantly oxygenated by the lipoxygenase. Fatty acid cyclooxygenase can be considered as an atypical lipoxygenase incorporating two molecules of oxygen into arachidonic acid. Therefore, the cyclooxygenase will also be discussed in comparison with lipoxygenase enzymes in this review article. A guideline for the nomenclature of 0ros;aglandin enzymology is given in Ref. 11. '

.

~,

J~

'~

oo.

OOH

~J(S,}.HPETE

Fig. 1. Mammalian lipoxygcnase.

The first iipoxygenase studied was originally termed a lipoxidase, was isolated and crystallized from soybean [1], and its catalytic properties were extensive!y investigated [2]. In a review article published in 1963, A.L. Tappel noted that lipoxidases were apparently absent in animal tissues [2]. This view was not to remain long because at that time the chemical structures of arachidonate-derived prostaglandins were just being elucidated [3] and many investigators began studying arachidonate metabolism in animal tissues. The lipoxygenase nature of prostaglandin-H synthase was soon demonstrated by isotope tracer experiments [4] and comparisons were made with this enzyme and the soybean lipoxygenase [5]. Later, human [6] and bovine [7] platelets were found to contain lipoxygenases which oxygenated carbon-12 (C-12) of arachidonic acid. When the biosynthetic pathway of leukotrienes was finally determined, it was found to depend on the initial TABLE

I1. Stereoehemistry o f lipoxyge ]ase reactions

Stereospecificity of hydrogen efimination

11-4.

Stereospecific elimination of one of the two methylene hydrogen atoms from a 1,4-pentadiene structure is characteristic of the lipoxygenase reaction. This was first shown by an isotope tracer experiment with the soybean lipoxygenase by using [13DR-'~H] and [13LS3H] 8,11,14-eieosatrienoie acids [5]. As illustrated in Table I, the stereoselective elimination of hydrogen has been experimentally shown in each lipoxygenase reaction.

I

Stereo.~pecific hydnJgcn dimmation in the lipoa3'gemtse and L TA symhase reactions Enzy,,,u activity

Hydrogen abslraction

Ref. OOH

5-Lipoxygcnase

7, ~%vSCOOH

H

~

7.proSH

~

~

OOH

HR.~ , ~ , , # , ~ . i COOH 5.6-LTA synthase

H

s

'

lo.proR

~

~

H ~

~

~ ~ f C O O H

/ ~ # 7 ~ . . , ~ j CO0 H C

~

O

O

H

~/%,¢'V

~'~ HOO..~HR A ~ . ~

"";~Tv

-

V

V

COOH

lO-proS H

_

~

-

-=,-

15-Lipoxygenase

~

co OH ~

~ O O H Cyciooxygenasc

13-pro$

)

"

18

HR

R(/,--~R-.~~¢ COOH ~

5 OOH

13-proSH

~

~3

H

, ; . ~. ... .

17.18

j..~,~vAv ~"

14.15-LTA synl hast OOH

|3- If~

H /~#==,%/~pCOOH

lO-proS

12-Lipoxygenasc -

12

~

I~,~~_.~ c 0 OH O.~.~-~ HR ~)OH

4

I i ~,~ II-~

t

., . . . . . . . . . .c: ... -.

,)ra,(,/,natiotl

The oxygenated product of lipoxygenasc has an asymmetric carbon, and the lipoxygcnase reaction occurs stereoselectively producing a hydroperoxide of either R- or S-configuration. With arachidenic acid as substrate 15S-HPETE is produced by the soybean lipoxygenase [5] and by rabbit reticulocytc 15-lipo~'genase [19]; 12S-HPETE is formed by the 12-1ipoxygenases of human [6] and bovine [7,20] platelets and ot porcine (C. Yokoyama et ai., unpublished data) and bovine [20] teukocytes; and 5S-HPETE by the human leukocyte 5-1ipoxygenase [8]. Antarafacial relationship was indicated between the hydrogen abstraction and the oxygenation [17]. As a hydrogen atom leaves from one side of the substrate molecule, an oxygen molecule enters from the other side. In the cycloox'ygenase reaction, the intermediate 1l-peroxy radical is presumed to be of the R-configuration, and PGG,, the final product, contains a 15S-hydroperoxide [4]. in contrast to the stereospecifity of the lipoxygenascs, those cytochromes P-450, which hydroxylate arachidonic acid, produce mixtures of R- and S-hydroxy acids [211. It should be noted that the oxygenation catalyzed by the bovine leukocyte and platelet 12-1ipoxygenascs is not 100% stereoselective and that minor amounts of 12RHPETE anomer are also produced [20]. IlL Liooxygenases as m u l t i - f u n c t i o n a l e n z y m e s

The multiple catalytic activities of plant and mammalian lipoxygenases have been previously reviewed in

detail [22-26] and are summarized in Table !I. Arachitionic ,Md ca, ~'." o ~ e n a t c d not only at a major site (C-12 for 12-lipoxygenase and C-15 ter L~-iipuxygenase) but also at altereative sites (C-!5 (or 12-1ipoxygenasc [2728] and C-12 for 15-1ipo~'gena~e [29]). Therefore. more than one product can be formed by a singlc enzyme. Secondly. the primaD' hydropcroxy product of some lipoxygenases can be further oxygenated at additional carbon atoms by the same enzyme: for 2xample, 15-HF'ETE is oxygenated at either C-8 or C-14 by 12-1ipoxygenase [27,28] and 15-1ipoxygcnasc [29], and 5-HPETE is oxygenated at C-6 by 5-1ipoxy.genase [30]. Thirdly, the primary hydroperoxy product can be transformed to an epoxy acid. This process invoIves the loss of H and HO from the hydroperoxy substrate (equivalent to the loss of H.,O) and leads to the formation of an epoxy acid with a conjugated triene. Epoxide formation by 5-1ipoxygenase is physiologically important and is required for synthesis of LTA4 [31-33], the precursor of bioactive LTs [36]. Epoxidation of 15-HPETE is also catalyzed by the t2- and 15-1ipoxygenases producing 14,15-LTA 4 (14,15-epoxy-eicosa-5,8,10,12-tetraenoic acid) [27-29]. As illustrated in Table I, the 5-1ipoxygenase abstracts the proR hydrogen from C-10 of 5-HPETE to form LTA.a [14- !6], whereas the 12-1ipoxygenase abstracts the pros hydrogen from C-10 of 15-HPETE to form 14,15 LTA4 [18]. A fourth activity of the lipoxygenase is to cleave C-C bonds next to hydroperoxy groups. Two proSucts are formed; an aldehyde and an alkane. For example, 13-oxotrideca-9,1 l-dienoic acid and pcntane are produced from 13-hydropcr3xy-9,1!-oc-

TABLE II Variou~ reucdon.~ , aqdy=ed by l i p ~ ' g e n a s e s as m u h i - f i o w t i o n a l e n : y m c s

Reactions

Exampies

sites in addition to the major site ( * )

the primary hydroperoxy product

HOd,"

Re f.

15-1ipo~genase

29

12-1ipo~gcnase 15-lipoxygenase

27,28 29

! 2-1ipo~0ger.a.se 15-1ipoxygen:lse

_%_8 29

15-1ipoxygun:lse

35

£)OH

~/~.qtt"~'%,~Ps~---t..: :. ~O!.1 HOd OOH

primary hydropero~ product to an epoxy acid

hydropcroxy product to an aldehyde and an alkane

Enzymes

6OI4

V ~

VVV~V 0014

VV

y\V 0

vvvv

120 types of enzyme. A previous study by Nugterep on bovine platelet 12-1ipoxygenase showed that (Table If'l) the enzyme is much less active with C18 fatty acids (linoleic, oMinolenic and y-linolenic acids) in comparison with arachidonic acid [7]. This finding was confirmed later by a purified enzyme [20]. This is also the case for the human platelet 12-1ipoxygenase [41]. An earlier work by Hamberg using a suspension of a large number of human platelets [42] showed ox3,genation of 6,9,12-oetadecatrienoic acid at positions 10 and 13, but the reaction rate with this substrdte was not quantitatively mentioned in comparison with arachidonic acid. An experiment with a human platelet suspension demonstrated oxygenation of 4,7,10,13,16,19-docosahcxaenoic acid at positions 14 and 11 with about half the rate of arachidonate 12-oxygenation [43]. The report is consistent with a finding with a purified enzyme [41]. In contrast, the 12-1ipoxygenase of porcine leukocytes has a broader substrate specificity reacting with C18- and C22-unsaturated fatty acids as fast as arachidonic acid [27,44]. It should be noted that porcine platelets have no 12-1ipoxygenase [45,46]. Walstra et al. have reported the presence of two 12-1i9oxygenases in bovine platelets and teukocytes, which were distinguishable by their reactivities with linoIeic acid [47].

tadecadienoic acid by 15-1ipoxygenase [35] and 12oxododeca-5,8,10-trienoic acid and presumably 2-octene are produced from I2-HPETE by 12-1ipoxygenase [34]. IV. Substrate specificities of lipovygenases Soybean lipoxygenase has a broad substrate specificity [37]. As listed in Table Ill, the enzyme is active with nt,:,lerous unsaturated Cts, C:0 and Czz fatty acids. Oxygenation sites for the soybean enzyme has been shown to be at C-t3 of tr-linolenic acid and at C-15 of arachidonic acid [5]. Thus, the soybean lipoxygenase is most like the mammalian 15-1ipoxygenases. Rabbit reticulocyte 15-1ipoxygenase also [19] shows a broad substrate specificity in terms of the carbon chain length

[38].

In contrast, the 5-1ipoxygenases from both rat and guinea pig react predominantly with C20 fatty acids [39,40]. These enzymes oxygenate 5,8,11-eicosatrienoic acid at C-5 almost as actively as they do arachidonic acid [39], whereas 8,11,14-eicosatrienoic acid is oxygenated at C-8 and a comparatively poor substrate [8,40]. Studies on the substrate specificity of 12-1ipoxygenases demonstl"ated the occurrence of two distinct TABLE

Iii

Subsrrate Specificities of iipoaygenases Vm~.~ v a l u e s a r e c o m p a r e d w i t h a r a c h i d o n i c a c i d as t 0 0 % Substrates

5-Lipo~genase

12-Lipoxygenase

RBL cell

porcine leukocyte

double bond

18

9,12 6,9.12

8 -

13 -

21)8 172

69 100

9.12,15

7

ii

f119

56

8,11

-

-

11,14

-

-

82 . 11 -

-

125 92 130

44 -

43 -

144 -

55 36

100

11}0

100

177

116

16.19

2

5-14ETE 5-HPETE 12-HETE 12-HPETE 15-HETE t5-HPETE

211

5,8,11 7,10.13 8,11,t4 11,14,17 5,8,11,14 5,8,11,14, 17

22 20

g u i n e a pig leukocyte

.

.

15-Lipo~genase

bovine leukocyte

Carbon number

-

.

bovine trachea

bovine platelet

human platelet

soybean

rabbit reticulocyte

130 51 103

310 280 200

11

51

5

2

n,d.

32 17

72 46

14 5

2 2

4 n.d.

15

29

26 5

. 2

. n.d.

-

-

81

-

. 71~

.

. 98

.

. i 13

60

7

27

-

380 60 590 300

2 10t3

n.d. i00

73 I00

220 I00

.

-

.

-

.

28

32

100

100

100

|00

36,

67

73

57

60

94

107

119

-

-

-

56

92

91

14

7

40

122

80

-

-

87 -

51) 127

15

-

-

2

3

-

-

-

-

-

1 I 2 58

18

2

-

-

39

41)

44

27

20

37

38

4.7,10,13.

Reference n.d., n o t d e t e c t a b l e .

.

.

. -

48

.

. -

7

. 6

20

7

41

t2t TABLE IV

V. Prosthetic groups and cofactors of lipox~genases

Two types of arachidonate 12-1ipoxyge,rase

V-A. Iron Leukocyte-type

Pialelct-type

Sub~tra:z specifL::y C t~ C2o

active active

alm~st im~ctivc active

Immunogenicity anti-leuko~'te enzyme anti-platelet enzyme

reactive unreactive

unreactive reactive

Distribution human bovine porcine canine

leukocytes, trachea leukoeytes, pituitary leukoc~'.es, cerebrum

ptatelets platelets platelets

These findings were confirmed and extended with the immunoaffinity-purified enzymes (Table 1I!). The bovine leukocyte 12-1ipoxvgenase has a broad substrate specificity like the porcine leukocyte enzyme, while the bovine platelet 12-1ipoxygenase is almost inactive w~th CiS-fatty acids [20]. The bovine leukocyte and platelct enzymes can be further distinguished by their differential immunogenicities, reaction time-courses and heat stabilities [20]. A monoclonal antibody raised against the porcine leukocyte 12-1ipoxygenase [46] cross-reacts with the bovine leukocyte enzyme, but not with the bovine platelet enzyme [20]. On the other hand, a monoclonal antibody raised against the human platelet 12-1ipoxygenase, cross-reacts with the bovine platelet enzyme, but not with the bovine leukocyte enzyme [20]. Monoclonal antibodies to the 12-1ipoxygenase have been utilized for immunoaffinity-purification of the enzyme from porcine pituita~ [49] and from bovine trachea [48]. These enrymes show a subs~rate specificity similar to thzt of the leukocyte enzyme. Thus, as summarized in Table IV, 12-lipoxygenases can be classified so far into two types (leukocyte-type and platelet-type) on the basis of their substrate specificities, immunogenicities and other properties. The leukocyte-type 12-1ipoxygenases have been found not only in leukocytes, but also in other tissues as mentioned above. The platelettype 12-1ipoxygenases have so far been found only in platelets. Both types of enzymes are present in bovine tissues and canine tissues (the leukocyte-type in leukocytes and cerebrum and the platelet-type in platelets) [50]. However, only the platelet-type is found in humans and only the leukocyte-type in porcine tissues. A characteristic of the rabbit reticulocyte 15-1ipoxygenase is its reacti-,,ity with phospholipids [51,52]. 15Lipoxygenase preparations of human polymorphonuclear lev~ocytes, soybean and rabbit retieulocytes o~-genate the (2-15 of araehidonate moiety esterified in phosphatidyicholine [53,54].

The content of non-heine iron in the soybean lipox-ygenase was previously reported [55-57]. Results of iron analyses of mammalian lipoxygenases are as follo,,vs: abeut ! atom per mol of rabbit reticulocyte 15-1ipoxygenase [24], 0.74 atom of iron per tool of porcine leukocyte 12-1ipoxygenase [58], and 1.1 or 0.5 atom of iron per tool ef recombinant 5-1ipoxygenase of human origin [59,60]. The hemoprotein nature of the ~clooxygenase is well known [61,62]. V-B. Peroxide acticators

In the course of the linoleat¢ oxidati¢,n by soybean Iipoxygenase. there is a short induction period required for full activity. This time-lag can be abolished by the addition of a catalytic amounts of hydroperax3,1inoleic acid [63]. it has been hypothesized that the hydroperoxide is required for oxidization of the inactive ferrous enzyme to the active ferric enzyme [64]. However, when the enzyme concentration is in excess of the peroxide concentration, both the ferrous and tl:e ferric forms of the soybean lipoxygenase are present and active [65]. Similarly, the porcine leukocyte 12-1ipox3,genase requires a lag phase of up to 30 s to be fully active, and this lag can be abolished by the addition of 1 ptM 12-HPETE [27]. Such an effect of hydroperox), fatty acid is also observed with the human leukocyte 5-tipoxygenase [66] and the rabbit reticulocyte 15lipox3,genase [67]. In a whole-cell experiment the human platelet 12-1ipoxygenase exhibited a lag phase in the presence of indomethacin [17]. This observation suggests an intracellular activation of 12-1ipexygenase by the cycloox~genase peroxyproduct. The cyclooxygenase reaction is triggered and accelerated by endogenously produced prostaglandin G (a hydroperoxy prostaglandin) or by added HPETE [68]. V.C. Calcium

Requirement for calcium ion at millimolar concentrations was first found with crude cell-free preparations of the 5-1ipox,s,genase [69]. This calcium requirement is also observed with other purified 5-1ipoxygenases [13,32,33,70-72], although the 12-1ipoxygenases and 15-1ipoxygenases do not require calcium ion except for their crude preparations [933]. An interesting observation to explain the role of calcium ion is the Ca'--+-dependant translocation of 5-1ipoxygenase from the cytoplasm to the membrane in leukocytes [74]. Treatment of human ieukocytes with an ionophore results in the loss of 5-1ipoxygenase protein and activity in the cytosol and the accumulation of the enzyme protein in the cell membranes.

122 V-D. A T P

nucleotide triphosphates, but ATP is the most active

Calcium-dependent 5-1ipo.,o/genase activity is stimuIatcd by the addition of ATP and the stimulatory effect of ATP is observed only in the presence ,ff calcium [40]. ATP can be replaced by ADP, A M P and other

[40]. A l t h o u g h t h e f u n c t i o n o f A T P is p o o r l y u n d e r s t o o d [40], t h e s t i m u l a t o r y e f f e c t , w h i c h w a s first f o u n d with a crude enzyme, has been confirmed with purified e n z y m e s f r o m v a r i o u s s o u r c e s [13,32,33,39,72]. T h e requirement of calcium and the stimulatory effect of

TABLE V Complementan.' and genomic DiVAs for mamr~'(tlian lipox-ygenases Enzyme

Species

Library

Primary structure amino acids

5-Lipoxygenase

12-Lipoxygenasc

15-Lipoxygcnasc

('ych)t)xygcnase

human

lung. placenta

M,

673

Expression ReL

77856

(811)

vector/host

Gene Ref.

pVL941/Sf-9 insect cell p K C / E. coli plY 169/ S. cere('isiae pRI35/ Osteosarcoma pJVETLZ/Sf9

(81)

ttL611

674

Ca 780t10

(86)

ral

RBL

6"M

Ca 77600

(89)

porcine

leukocyte

662

74911

(90)

pKK223/E, colt

(911

hu m,'m

ilEL

663

Ca 75000

(93)

(93)

plalclct

663 662

75 5 i 3 75 590

(94) (951

pCDNA | / COS.M6 oUCI9/E, colt CDMS/COS

human

rcticulocylc

661

Ca 74600

(96)

rabbit

rcticuiocyte

662

Ca 75(XR1

(98,99)

ovine

seminal vesicle

human

murine

chicken murine

15-Lipoxygcnasc L-I soybean L-2 L-3 pea

61111-24 61~1-24 599(-23) gcnomic library 599 (-231 in EMBL3 pl;~lelet/HEL 599-23 platelct 599 swiss 3T3 6112 ( - 26) NHt 3T3

fibroblast swiss3T3

66013 * 66175 * 68598"* 68548 **

(11)1) 1102) 11031 111171

pCD/COS- I

69995

(!!18) (226) (11141

pGEM7ZR-)/ COS-M6

promotor

Ref.

14

(82)

GGGCGG

(83)

14

(92)

GGGCGG. CCGCCC, AP-2

(92)

14

(I(X)) TAT'ITA, CACCC, GGGCGG

(I00)

I1

(107)

(87) (88)

(94) (951 (97) (97)

( t114-108)

( I1181

1109) GGGTGG, (I119) AP- i, nGRE,DRE

603 ( - 17) 694

838 865 859 861 864

ReL

(84) (85)

human

pR135/ Osteosarcoma pJC264/E, coil

exon

(1 III) ( 11 I)

94038 97036 96541 97628 97134

* Molecular weight fl)r protein including no signal peptide. ** Molecular weight for protein including signal peptide.

(113) (114) (115) (116) ( I 17)

(! 12)

TTAAAA. 11t2) GGGCGG. TGCGTGG

123 ATP are observed not only in the 5-oxygenase activity but also in the leukotriene A synthase activity [13,31-

331. V-E. 5-Lipoxygenase-acrit'athrg proiein (FLAP) A new specific inhibitor of leukotrienc synthesis (MK886) in intact cells does not inhibit the catalytic activity of ceil-free 5-lipoxygenase, but inhibits the translocation of the enzyme from the cytosol to the cell membrane [75]. By the use of MK886, a novel protein of 18 kDa was isolated from detergent-solubilized extracts of rat leukocyte membrane [76]. A complementary DNA encoding the MK886-binding protein was isolated, and the co-expression of both the MK886-binding protein (now referred to as five-lipo~:ygena,,;e activating vrotein, FLAP) and the 5-1ipox'ygena3e was necessary for leukotriene synthesis in transfected cells [77]. FLAP is found only in cells known to produce leukotrienes and not in cells which do not [78]. Ret. 79 is a recent review article co:~cerning FLAP. VI. Molecular structure of lil~o~genases Recent reports on molecular biological studies of lipox3,genases are summarized in Table V. eDNA for cyelooxygenase of ovine seminal vesicles was cloned, and the primary structure of the enzyme was deduced from the nucleotide sequence of the eDNA [101-103]. The site of acetylation by aspirin was located at serine-530 [101-103]. The site-directed mutation from the serine-530 to alanine did not affect the enzyme activity, suggesting the non-involvement of the serine residue in the enzyme catalysis [10a.]. The tyrosine-385 was proposed to be involved in the 13-proS hydrogen abstraction [105]. The site directed mutation also suggested that histidine-309 was the axial hemc ligand and histidine-207 or 388 served as the distal heine ligand [106]. According to a computer-assisted homology search, the N-terminal region of the ovine ~clooxygenase shares a sequence homology with epidermal growth factor [118]. Genomic DNAs encoding the human cyclooxygenase (40 kb) and the murine enzyme (22 kb) were cloned, and their nucleotide sequences were determined. Both genes consist of I1 exons [107109]. The murine cyclooxygenase gene was analyzed for its 5'-flanking regulatory sequences [109]. in cuitared epithelial cells of sheep tracheal mucosa, a 4.0 kb mRNA was detected by Northern blotting utilizing cyclooxygenase eDNA probes at lower stringency. The 4.0 kb mRNA was distinguished from the previously known 2.8 kb mRNA corresponding to the cyclooxygenase protein [119]. The presence of a new form of the cyclooxygenase enzyme (a 603-amino acid protein with 59% amino acid identity with ovine cyclooxygena.~e) was shown by detection of a 4.1 kb

mRNA expressed in chicken embryo fibroblasts infected with Rous sarcoma virus [110]. Another eDNA encoding a 604-amino acid protein with a sequence identity of over 60% with murine, ovine and human cycloo.x3,genases was cloned from S'~ iss 3T3 fibroblasts treated with phorbol ester [I t 1]. Microsomes of COS-1 ceils transfected with this eDNA exhibited both the cyclooxygcnasc and hydroperoxidase activities. The cloned gcnomic DNA had an exon-intron structure similar to that of the previously known cyclca~xygcnase [i121. A eDNA clone for 5-lipoxygenase was isolated from human eDNA libraries [80,86] and the primary structure of a 673-(80) or 674-(86) amino acid protein was deduced. A eDNA clone encoding 670 amino acids was also isolated for the enzyme of rat basophilic leukemia cells [89]. The 5-1ipo~genase cDNAs were expressed in mammalian [87] and insect [~!] e,lls. The recombinant enzyme transforms arachidonic acid to 5-HPE'I'E and UFAa, and shows a dependence on calcium ion and ATP [81,87,88]. This finding serves as independent evidence that both 5-1ipo~genase and LTA synthase activities are attributed to a single enzyme protein. A eDNA encoding human 5-1ipox'ygenase was also expressed in Escherichia coil [84] and Saccharomyces cercisiae [85]. Essential role of conserved histidine residues as possible iron ligands was examined by the method of site-directed mutation [81,120,121]. Replacement of histidines-367, -372 and -551 [121] (the former two corresponding to 368 and 373 in Ref. 121)) by serines led to the production of inactive proteins, while histidines-362, -390 and -399 [ 121] (363, 391 and 400 in Ref. 120) could be substituted by gerines without the loss of enzyme activity. Mutation of glutamine-558 and the C-terminus gave mutated proteins with only a small residual activity [121]. A genomic DNA of human 5-1ipoxygenase was isolated and found to consist of 14 exon.~. The putative promoter region contained no TATA and CAAT sequences [82]. Further studies on the 5-1ipox3,genase gone promoter demonstrated that five repeated GC boxes (the putative Spl binding sequence)were esseatial for transcription [831. A eDNA encoding rabbit reticulocyte 15-1ipoxygenase was isolated [98,99]. A genomic DNA with 14 exons for the rabbit reticulocyte 15-1ipoxygenase was isolated [i(10]. A full-length eDNA for human reticuIocyte 15-1ipoxygenase was also isolated [96] and expressed in osteosarcoma cells and E. coil [97]. In view of the conserved differences in the isoforms of 15- and 12-1ipoxygenases, replacement of methionine-,ll8 by valine together with mutations at the neighboring amino acids 416 and 417 of human 15-1ipoxygenase gave an enzyme which catalyzed 12- and t5-oxygenation of arachidonic acid in a ratio of 15: i [122]. eDNA clones for plant 15-1ipoxygenases were isolated and their pri-

124 TABLE VI Comparison of the primary stntctures of carious lipoxygenases Enzymes

Human 5-LOX

Aminoacid sequence identity human rat human 5-LOX 5 - L O X 12-LOX I00 100

Rat 5-LOX

porcine 12-LOX

human 15-LOX

Potential iron-bindingsites rabbit s o y b e a n His-rich Cys-rich 15-LOX 15-LOX sequence sequence 362-399 363-400 none

100

Human 12-LOX

41 40 42

39

Porcine 12-LOX

40

39

Human 15-LOX

61

1O0 100 100

66 65 66

66 65 65

62

66

100

86

79

100

Rabbit 15-LOX Soybean 15-LOX

Ref.

80 86

42

362-399

none

89

25

355-392 355-392 354-391

532-544 532-544 531-543

94.123 93 95

356-393

533-545

90,123

355-392

532-544

96

355-392

532-544

99

39 1130

100

493-530 (L-I) 522-599 (L-2) 513-550 (L-3)

114

LOX, lipoxygenase; His-rich sequence, His-(Xaa)4-His-(Xaa)4-His-(Xaa)iT-His-(Xaa)s-His;Cys-rich sequence. Cys-(Xaa)~_4-C'~s-(Xaa)2_ls-a(Xaa)~_4-a (where a is either hislidine or cysteine).

m a l t structures were deduced from the nucleotide sequences: soybean lipoxygenase-1 [113], soybean lipoxygenase-2 [!14], soybean lipoxygenase-3 [115] and pea seed lipoxygenase [116,1 I7]. A e D N A clone for porcine leukocyte 12-1ipoxygenase was isolated, and from its nucleotide sequence the primary structure of the enzyme protein was deduced and shown to consist of 662 amino acid residues [90]. An expression vector was constructed from the 12-1ipoxygenase e D N A with tac promoter, and the enzyme was expressed in E. coli [91]. A genomic D N A of the enzyme was cloned and its nucleotide sequence was determined. The gene consists of t4 exons and 13 introns. The 5'-upstream region contains 9 G C boxes and 2 AP-2 binding sequences. Neither typical T A T A box nor C A A T box are found in this region [92]. A cDNA for 12-1ipoxygenase from human platelet (actually from human erythroleukemia cell) was cloned by three groups [93-95]. There are minor discrepancies in the number of amino acids and the molecular weight among the three reports as listed in Table V. The enzyme was expressed in COS cells [93,95] and E. coli [94]. 12-Lipoxygenase m R N A s from porcine leukocytes and human erythrolcukemia cells were distinguishable by Northern blotting utilizing cDNAs for the two lipoxygenases [94]. The result is consistent with the occurrence of two types of 12-1ipoxygenase distinguished catalytically and immunologically as described above.

The deduced amino acid sequences of various lipoxygenases were compared as summarized in Table VI. On the basis of the amino acid sequence identity, 12-1ipoxygenase of the leukocyte-type is closer to 15lipoxygenase (86% identity with human reticulocyte enzyme and 79% identity with rabbit reticulocyte enzyme) than to 12-1ipoxygenase of the platelet type (66% identity with human erythroleukemia cell enzyme). A well-conserved histidine-rich sequence is found in all lipoxygenases (Table VI) and this sequence has been discussed as a putative iron-binding site [81,89,90,94-96,99,114]. The site-directed mutation of these histidine residues was performed with 5-1ipoxygenase e D N A as described above [81,120,121]. In addition to this histidine-containing sequence, a short cysteine- and histidine-containing sequence was found in 12- and 15-1ipo~genases (but not in 5-1ipoxygenase) [123]. This sequence is similar to the structure known as the 'zinc-finger motif' [124].

VII. Regulation of arachidonate metabolism by enzyme induction Arachidonate release is triggered by the phospholipase reaction, and then the released arachidonic acid is the substrate of the cyclooxygenase or lipoxygenase enzymes. According to many experimental observations only part of the available arachidonic acid is utilized by the cyclooxygenase or lipoxygenase. In particular, the

125 cyclooxygenase and lipoxygenase reactions are ratelimiting after the arachidonate release. If the activity of the cyclooxygenase or lipoxygenase increases, the rate of arachidonate metabolism is enhanced and the amount of bioactive product (prostaglandin, thromboxane or leukotriene) increases. Induction of cyc!ooxygenase was earlier mentioned by Levine and his co-workers in a paper entitled 'Induction of fatty acid cyclooxygenase activity in canine kidney ceils (MDCK) by benzo(a)pyrene' [125]. Many other reports described increased prostaglandin synthesis, namely, either the prostaglandin synthesis from endogenous arachidonic acid or the release of labeled prostaglandin from esterified radioactive arachidonic acid. Some of these reports may have shown phospholipase activation rather than enzyme induction. The first molecular biological approach to the cyclooxygenase induction was reported for mouse mastocytoma cells, and the increase in the cyclooxygenase mRNA was shown by a combination of cell-free translation and immunoprecipitation [ 126]. Recently, molecular bioingical techniques, especially gene-cloning and monoclonal antibody, have been applied to studies on the induction of enzymes in the arachidonate cascade. The molecular mechanism of cyclooxygenase induction has been a target of these molecular biological approaches. These include induction by epidermal growth factor in rat smooth muscle cells [127,128], by interleukin-I in human dermal fibroblasts [ 129,130] and in human endothelial cells [ 131], by cAMP in mouse osteoblasts [132,133], by endotoxin in human blood monocytes [134,135], by phorbol ester in human umbilical vein endothelial cells [136], and by la,25-dihydroxyvitamin D-3 or phorbol ester in human promyelocytic leukemia cells [137]. A recent review article by DeWitt [138] summarizes a number of reports on the regulation of cyclooxygenase expression. An important finding derived from the studies on the cydooxygenase induction is concerned with the mechanism of prostaglandin synthesis inhibition by glucocorticoid. The previous concept of the glucocorticold-induced lipocortin, which was considered to directly inhibit the phospholipase enzyme, has been criticized and reconsidered recently (for review see Ref. 139). Bailey et al. reported a new type of translational control of the cyclooxygenase mRNA. A certain protein (e,g., lipocortin) is induced or activated by glucocorticoid and interacts with a highly conserved 3' untranslated region of the cyclooxygenase mRNA. The mRNA is converted to a nontranslated cryptic form. The cryptic form of the cyclooxygenase mRNA may be activated by phosphorylating the bound lipoeortin by the catalysis of tyrosine kinase of epidermal growth factor receptor. Ref. 140 is a review on this subject. Little has been reported about the induction of lipoxygenase, it was reported earlier that the platelet

!2-Iipo×ygenasc activity was stimulated by adminis:ration of 17/3-estradiol to the rat [14l]. Recently, induction of 12-1ipoxygenase mRNA was demonstrated in human crythroleukemia cells differentiated by the addition of phorbol ester [95]. Epidermal growth factor enhanced a microsomal 12-1ipoxygenase activity in human epidermoid carcinoma cell A431 [142]. When 5lipoxygenase eDNA was cloned from HL-60. the cell was differentiated by treatment with dimethylsulfoxide aad 5-tipoxygenase mRNA was induced [86]. Recently, 5-1ipoxygcnase activity was expressed in human tonsilar B cells and lymphoblastoid B cell lines when these cells were treated with cytokines [143]. This finding was confirmed by Western and Northern blottings [144]. An analytical method by ouantitative polymerase chain reaction was developed for determination of mRNAs for 5-, 12- and 15-1ipoxygenases and cyclooxygenase [145]. This method can by applied to investigate the dynamic aspects of lipoxygenasc mRNA in cell differentiation and various diseases. A recent paper reported that interleukin-4, among various biofactors tested, induced 15-1ipoxygenase mRNA and protein in cultured human monocytes [I46]. VIII. Distribution of lipoxygenases and cyclooxygenase in various mammalian tissues Extensive and precise studies on enzyme distribution in various organs are helpful to understand the physiological function of the enzyme. Assays of the enzyme activity with crude preparations of various organs are sometimes disturbed by the presence of endogenous inhibitors of the enzyme. Peroxidase-linked immunoassays were developed for quantitative determination of porcine 12-1ipoxygenase [46,49] and 5lipoxygenase [147] and bovine cyclooxygenase [! 48] and the results obtained by these assays are presented in Table VII. By far the highest contents of 12- and 5-1ipoxygenases are found in porcine leukocytes and con:;iderable amounts (1-10% of the enzyme amount in leukocyte) of enzyme are present in alimentary tracts, lung, thymus, lymph node, spleen and some parts of the brain. The enzyme immunoassay of cyclooxygenase demonstrated a distribution of the enzyme in bovine organs similar to that previously investigated by the assay of prostaglandin biosynthesis activitiy [ 149]. Further studies by immunohistochemical approaches are required to clarify what type of cell contains lipoxygenase or cyclooxygenase in each organ. A number of papers have been published reporting the localization of cyclooxygenase in various mammalian organs: epithelial cells of renal collecting tubules and other types of renal cell [150-153], endometrial epithelium with a time-dependent change of the enzyme content [i54-159], decidualized stroma cells in uterus [160,161], granuiosa cells in ovary [162-165], epithe-

126 T A B L E VII Distribution o f 12- and 5-1ipoxygenases and ~Telo¢.~'gel~ase as crambtcd by enzyme imnutnoassay

Organs

Porcine 12-1ipoxygenase

Porcine 5-1ipoxygenase

Bovine cyclooxygenase

Leukoeytes Platelel Esophagus Stomach Small intestine Caecum Colon tJver Gall bladder Pancreas Lung Renal medulla Renal cortex Urinary bladder Vesicular gland Uterus Ovary Thyroid gland Adrenel gland Thymus Lymph node Spleen Aorla Heart Skeletal muscle Skin Anterior pituitary Posterior piluitary Pineal glt, nd Neocortcx ltippocampus Hypothalamus Thalamus Cerebellum Pons Medulla oblongata

!01}(f/c) n.d. n.d. 4.9 17.4 (I.2 0.6 3.7 < (1,1 0.2 2.7 n.d. n.d. 0.3

10{)(¢?;)

n.d.(%) 28,8 2.7 4.0-14.5 27.6-46.7 60.0 29,o 2.2 50.1 n,d. 41.0 28,5 n.d. 10.8 !171 3.1 n.d.

Reference

46.49 *

(I.4 7.4

1(I.0 1 I.!

n,d. n.d, n.d. < (1.1 5.5 3,9 2.0 n.d, < 0.I < (1,1

[1.4

11.1

6,6 4.1 2.4

n.d. 4,0 7.5 7.5 8.0 n,d, (I.3 0,7 11.2 0.4 11,2 6.9 1,2

5.6 * i).6 * 0,05 * < 0.03 * < I),03 * (I.II2 * 0.(15 (1.(18 0,(18 0.18

*

0.8 O. 1

* * *

11.5 147

148

n.d.. nol delectable.

lium of epididymis and vas deferens [166], lamina propria, capillary endothelial cells and muscle cells in stomach [167], muscle cells in small intestine [153], glia [168,169] and neurons [169] in brain, and endothelial cells in 20-fold higher amounts than smooth muscle cells in bovine aorta [170]. As for the subcellular localization of the enzyme, electron microscopic observations demonstrated the localization of eyclooxygenase in the endoplasmic reticulum and nuclear membrane (but not the mitochondrial or plasma membrane) of Swiss mouse 3T3 fibroblasts [171] and in the secretory granules of rat connective tissue mast cells [172]. A predominant occurrence of the 5-1ipoxygenase activity in granulocytes as described above was sup-

ported by an immunohistoehemical screening in porcine tissues [173]. Neutrophils and eosinophils in peripheral blood are positively stained, but lymphocytes are unstained [173]. In porcine ileum, which contains a considerable amount of 5-1ipoxygenase as examined by the peroxidase-linked immunoassay [147], the majority of the stained cells are eosinophils and mast cells resident in the lamina propria mucosae, whereas parenchymal cells are not stained. 5-Lipoxygenase is localized in the cytoplasm but not in the plasma membrane and subcellular organelles of the positively stained cells [173]. In addition to these cells, certain bronchiolar or bronchial epithelial cells are clearly stained in porcine lung [173]. Porcine pancreas has a 5-1ipoxygenase activity associated with the 1000 X g pellet and 105000 x g supernatant. Langerhans islets are not stained, and infiltration of 5-1ipoxygenase-positive leukocytes is rarely observed. In contrast, acinar cells are positively stained, and the enzyme is localized along the nuclear membrane observed by electron microscopy [174]. All the cells in the endometrium and myometrium of human uterus [157] and granulosa cells in human ovary [165] are 5-1ipoxygenase-positive. Porcine tissues were immunohistochemically screened for 12-1ipoxygenase with an antibody raised against porcine leukocyte 12-1ipoxygenase [175]. In peripheral blood cells, the enzyme is found in neutrophils and monocytes but not in lymphocytes, platelets and erythrot3,tes. The enzyme is localized in the cytosol of these positively-stained cells, but is not detected in the plasma membrane, nuclear membrane, endoplasmie reticulum and other organelles [175]. In several other porcine organs with considerable amounts of 12-1ipoxygenase such as alimentary tract, lymphatic organs, ovary, lung and liver [46], resident mast ceils and granulocytes infiltrating the interstitial tissues are immunostained, but the enzyme is not detected in parenchymal cells of these organs [175]. An exception is anterior pituitary, in which certain parenchymal cells with granules are positively stained [49]. Epithelial cells of bovine trachea, in which the leukocyte-type 12lipoxygenase is present [48], are also immunostained [176]. A polyclonal antibody against recombinant 15lipoxygenase of human reticulocytes was applied to immunocytochemical localization of 15-1ipoxygenase. Mature reticulocytes of rabbit, human eosinophils and tracheal epithelial cells are positively stained [177].

IX. Physiological roles of lipoxygenases Physiological roles of cyciooxygenase and 5-1ipoxygenase are well known. The former enzyme initiates the synthesis of various prostaglandins and thromboxanes, and the latter enzyme is responsible for the production of leukotrienes. However, the physiological

127 functions of 15- and 12-1ipoxygenascs are ,,,till subjects of investigations and discussions. A 15-1ipoxygenase was discovered and purified during the study on endogenous respiratory inhibitors in rabbit retieulocytes, and it was earlier proposed that the enzyme was involved in the degradation of rcticuIocy~e mitochondria during red cell maturation [178]. The oxygenated products from linolcic and arachidonic acids were found in the course of rcticulocytosis [179]. Lipoxins are trihydroxy derivatives of arachidonic acid with a conjugated tetraene. Lipoxin A4 (5S,6R, 15S-trihydroxy- 7E, g E, 11Z, 13 E-eicosatetraenoic acid) and lipoxin B4 (5S,14R,15S-trihydro×y6E.SZ. 10E,12E-eicosatetraenoic acid) and their isomers ;-ave been isolated [180]. Lipexin,,; ,~, and ~34 arc biologically active, for example, activating leukocytes and inhibiting NK cell activity. Refs. 181-183 are review artieles for lipoxins. Purified 15-1ipoxygenasc of rabbit reticuloeytes produces lipoxin B4 by 14R-oxygenation of 5,15-diHETE or double o~genation of 15-HETE or triple oxygenation of arachidonic acid [t84]. The 14Roxygenase and 14,15-1eukotriene A synthase activities of purified 12-lipoxygenase of porcine Icukocytcs are involved in the lipoxin production [185]. involvement of the 15-1ipoxygenase activity of human platelet 12lipox'ygenase was proposed in the transccllular lipoxin production by leukocytes and platelets [186-1871. Either a platelet suspension [187] or a 1130000 × g supernatant of platelets [186] transformed exogenous leukotriene A 4 to iipoxins. Human megaka:'7"~cytic cells (Dami) treated with phorbol myristate acetate or COSM6 cells transfected with a human 12-1ipoxygenase eDNA converted ieukotriene A 4 to lipoxins [188]. The quantitative substrate specificity study with the immunoaffinity-purified 12-1ipoxygenase of human and bovine platelets had much lower, if any, activities for lipoxin production from leukotriene A., as compared with the enzymes of porcine and bovine leukocytes which converted leukotriene A4 to lipoxins at 3 and 2% the rate of araehidonate oxygenation [41]. Lipoxygenase has been presumed to be involved in the oxidation of low-density lipoprotein responsible for atherogenieity. This was clearly shown with soybean lipoxygenase [189], and implicated in rabbit aortic endothelial cells [190] and human monoeytes [191] by the use of lipoxygenase inhibitors. By the use of eDNA and antibody for human reticulocyte 15-1ipoxygenase, it was demonstrated that 15-1ipoxygenase colocalizcd with epitopes of oxidized low-density lipoprotein in rabbit atheroselerotic lesions [192]. A similar observation was reported for human atherosclerosis [193]. However, there was a paper reporting that neither 5- nor 15lipoxygenase was required for the oxidation of low-density lipoprotein [ 194]. Production of 12-HETE by human skin in psoriatic region was reported earlier [195]. The stereochemistry

of 12-HE'FE was clarified later, and the production of 12R-I-IEFE was attributed to cytochrome P-450 [196]. Various biological activities have been reported for I2-HETE. For example, the migration of rat aortic smooth muscle ceils was stimulated specifically by a very low concentration (3-10-15 g/mi) of 12-HETE. 15-HETE was much less active, and 5-HETE was inactive [197]. A maximal stimulation of LH-RH release from rat median eminence was observed with 10 nM 12-HETE [198]. Melatonin synthesis was stimulated by HPETEs. A maximal effect was observed with 1 ta,M 12-HPETE and I5-HPETE, while 5-HPETE and various HETEs wcrc ineffective [199]. t2S-HETE (but not 12R-HETE) enhanced the adhesion of Lewis lung carcinoma celts to endothelial cells, subendothelial matrix and fibroncctin presumably by stimulating the expression a n d / o r activation of G p l l b / l i l a receptor [2011]. Two hydroxyepoxy compounds were found to be produced from 12S-HPETE [20t]~ and were referred to as hepoxilins: hepoxilin A.~ (8-hydroxy- 11,12-epoxy5,9,14-trienoic acid) and hepoxilin B~ (10-hydrox.'y11,12-epoxy-5,8,14-trienoic acid) [202-2114]. Hemoglobin- and heroin-catalyzed transformation of 12SHPETE to hcpoxilins was demonstrated [2115], but the enzymatic nature of hepoxilin synthesis has not yet been established. A variety of biological activities have been reported for hepoxilins [2116]. Hepoxilin A 3 was released from endogenous source during perifusion of rat pancreatic islets of Langerhans with glucose and was presumed to mediate the insulin release process [207]. Hepoxilin A 3 stimulated calcium mobilization in association with neutrophil activation [2118]. in connection with this report, hepoxilin A 3 stimulated phospholipase C of human neutrophils, which was involved presumably in the rise of cytosolic calcium [209]. A possible involvement of 12-1ipoxygenase metabolites as second messengers in neurotransmission was demonstrated with Aplysia sensory cells [210,211] and the active metabolites were identified as hepoxilin A~ [212] and 12-keto-5,8,10,14-eicosatetracnoic acid [213]. Hepoxilin A 3 blocked the release of norepinephrine from rat hippocampal slices [214]. In human adrenal glomerulosa cells, aldosterone production is stimulated by angiotensin !!, ACTH or potassium ion. Only angioten~in !I [l, ut not the latter two) stimulated production of 12-HETE (but not 15HETE), and the angiotensin ll-dependent aidosteronc release was inhibited by BW755C, a nonselective lipoxygenase inhibitor. These findings suggested an involvement of the stimulation of 12-1ipoxygenase pathway in the angiotensin ll-dependent aldosterone secretion [215-2t6]. These fin0ings with 15- and 12-1ipoxygenases are individually interesting. However, unlike cyclooxygenase and 5-1ipoxygenase, no metabolite with a specific biological activity and a stereoselect!ve ~tructure

128 e q u i v a l e n t to p r o s t a g l a n d i n s a n d l e u k o t r i e n e s has b e e n f o u n d as yet, a n d w e still d o n o t k n o w a n y g e n e r a l physiological f u n c t i o n o f 15- a n d 12-1ipoxygenases w h i c h is a p p l i c a b l e to v a r i o u s cell t y p e s o f m a n y a n i m a l species. In this review article t h e a u t h o r r e v i e w e d a n d c i t e d the papers on cyclooxygenases and lipoxygenases which n a d b e e n p u b l i s h e d u p to M a y , 1992. Refs. 61, 138, 217 a n d 218 a r e review articles c o v e r i n g s t u d i e s on cyctoo x y g e n a s e a n d Refs. 25, 26 a n d 2 1 9 - 2 2 5 c o v e r t h e r e p o r t s for m a m m a l i a n l i p o x y g e n a s e s .

Acknowledgements T h e a u t h o r is g r a t e f u l to Drs. A l a n R. Brash, Cecil R. P a c e - A s c i a k , T a n i h i r o Y o s h i m o t o , Y o s h i t a k a T a k a hashi a n d H i r o s h i Suzuki for t h e i r k i n d adivice a n d critical r e a d i n g o f this m a n u s c r i p t . T h a n k s a r e also d u e to Drs. D e n i s R i e n d e a u , D a v i d L. D e w i t t a n d M a r t y n J. Bailey w h o kindly p r o v i d e d t h e a u t h o r w i t h p r e p r i n t s o f m a n u s c r i p t s to be p u b l i s h e d . T o s h i y a A r a k a w a ' s assistance to r, r e p a r e t h e f i g u r e s a n d t a b l e s o f this m a n u s c r i p t is g r e a t l y a p p r e c i a t e d .

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Mammalian lipoxygenases: molecular structures and functions.

er B i o F h y s i c a A c t a . 1t28 (1992) 117-131 Igq2 Elsevier Science Publishers B.V. All rights reserved (1111)5-27,5(1/92/S(]5.00 117 Biochim...
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